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T H E R A P E U T I CS British Journal of Dermatology
Adalimumab for moderate to severe chronic plaque psoriasis: efﬁcacy and safety of retreatment and disease recurrence following withdrawal from therapy
K. Papp, J. Crowley,* J.-P. Ortonne, J. Leu,à M. Okun,à S.R. Gupta,à Y. Guà and R.G. Langley§
Probity Medical Research, Waterloo, ON, Canada *Bakersﬁeld Dermatology, Bakersﬁeld, CA, U.S.A. Nice University Hospital, Nice, France àAbbott Laboratories, Abbott Park, IL, U.S.A. §Dalhousie University, Halifax, NS, Canada
Kim Papp. E-mail: firstname.lastname@example.org
Accepted for publication
1 November 2010
Abbott Laboratories funded this study and participated in the study design, data collection, data management, data analysis, and preparation of the manuscript.
Conﬂicts of interest
The following conﬂicts are reported: K.P. with Abbott, Amgen, Astellas, Biogen, BoehringerIngelheim, Celgene, Centocor, EMD Serono, Genentech, Isotechnika, Johnson & Johnson, MedImmune, Merck-Serono, Schering-Plough and Wyeth; J.C. with Abbott, Amgen, Centocor, Genentech and Lily; J.-P.O. with Abbott, Centocor, Galderma, Janssen-Cilag, Leo Pharma, Meda Pharmaceuticals, Merck-Serono, PierreFabre, Schering-Plough and Wyeth; J.L., M.O., S.R.G. and Y.G. are employees of Abbott Laboratories; and R.G.L. with Abbott, Amgen, Astellas, Boehringer-Ingelheim, Centocor, Genentech, Novartis and Wyeth. DOI 10.1111/j.1365-2133.2010.10139.x
Background Adalimumab is effective for moderate to severe chronic plaque psoriasis; however, data regarding retreatment following withdrawal and subsequent relapse are limited. Objectives To evaluate the efﬁcacy and safety of adalimumab if interrupted and then resumed in patients with moderate to severe psoriasis. Methods Patients in a long-term adalimumab open-label extension study (NCT 00195676) who achieved a Physician’s Global Assessment (PGA) score of ‘Mild’ (2), ‘Minimal’ (1) or ‘Clear’ (0) were withdrawn from adalimumab and monitored for relapse to PGA of ‘Moderate’ (3) or worse. The subgroup of interest had stable psoriasis control, deﬁned as PGA of 0 ⁄ 1 for ‡ 12 weeks on every other week (eow) dosing before withdrawal. Relapsing patients were retreated with adalimumab (80 mg at week 0 and 40 mg eow starting at week 1). PGA, Psoriasis Area and Severity Index responses, fatigue, pharmacokinetics and immunogenicity were assessed. Results In total, 525 patients were withdrawn from adalimumab; the subgroup with stable psoriasis control comprised 285 patients. Of these, 178 relapsed (median = 141 days) before treatment reinitiation and 107 did not relapse. Patients without relapse by 40 weeks off therapy reinitiated adalimumab. Rates of PGA 0 ⁄ 1 after 16 weeks of adalimumab retreatment were 89% for patients without relapse and 69% for patients who relapsed. Relapsers experienced signiﬁcantly less fatigue after retreatment. Nine patients (3%) had serious adverse events (two were infections). No rebound or allergic reactions occurred. Conclusions Adalimumab-treated patients who discontinued therapy and subsequently relapsed had a good likelihood of regaining clinical efﬁcacy following adalimumab reinitiation.
The favourable beneﬁt–risk balance of biologic tumour necrosis factor (TNF) antagonists in the treatment of moderate to severe chronic plaque psoriasis has enhanced the therapeutic options available to physicians and patients confronted with this disease.1 Consensus regarding when and how these agents should be used in the management of psoriasis is evolving. The high level of skin efﬁcacy, accompanied by the potential for sustained control of comorbidities such as psoriatic arthritis and improved quality of life, are considerations that favour continuous use of these agents; however, even advocates for
continuous use recognize that there are circumstances in which interruption of therapy is warranted (e.g. prior to elective surgery, during a serious infection, or in planning for a pregnancy). The purpose of this study was to describe the efﬁcacy and safety of adalimumab after one or two prolonged treatment interruptions. Adalimumab is a fully human monoclonal antibody speciﬁc for TNF. It is currently approved for rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis and Crohn’s disease. The 52-week cliniÓ 2011 The Authors
BJD Ó 2011 British Association of Dermatologists 2011 164, pp434–441
2–5 Study design and treatment regimens Study M03-658 was conducted at 104 sites in the U. Physician’s Global Assessment. As part of the M03-658 study design. K. Papp et al. every other week. Physician’s Global Assessment. The maximum durations that any patient was enrolled in Periods O. open-label continuation study enrolled adult patients with moderate to severe chronic plaque psoriasis who participated in a prior adalimumab psoriasis study and had either prematurely terminated from one of those studies owing to relapse ⁄ loss of adequate response [studies M02-538. A greater percentage of patients rerandomized to placebo lost adequate response compared with those who received adalimumab continuously (28% vs. and efﬁcacy and safety outcomes. Flow from Period O to Period W to Period R. Table 1 Deﬁnitions of treatment periods and analysis populations Period O Period W Period R Stable psoriasis control (mITT population) mITT-W population mITT-R population Open-label period.2 At week 33 of REVEAL. Patients who completed REVEAL and eligible patients who had participated in other phase II and phase III adalimumab clinical trials could participate in the open-label extension study M03-658. M03-596. have been published. modiﬁed intention-to-treat. 435 cal trial REVEAL demonstrated the short. M03-656 (REVEAL)] or had completed the study and remained eligible [M02-528 ⁄ M02529. Details from the preceding adalimumab studies. the treatment withdrawal period (Period W) and the retreatment period (Period R). 1). monitored for disease relapse. eow. during which patients received adalimumab 40 mg eow or 40 mg weekly Withdrawal period.and medium-term efﬁcacy and safety of adalimumab in the treatment of moderate to severe psoriasis.A.. This multicentre. patients with a Physician’s Global Assessment (PGA) score ‡ 3 were discontinued from the study and patients with a PGA score £ 2 were Patients and methods Patients Institutional review boards at each participating medical centre approved the protocol. during which eligible patients (those with PGA of 0 ⁄ 1 ⁄ 2 at the end of Period O) were withdrawn from therapy and monitored for relapse (PGA ‡ 3) Retreatment period. PGA. W and R are deﬁned in Table 1.S. During Period O. Periods O. including inclusion ⁄ exclusion criteria. with the option to increase the dosage to 40 mg weekly if they had less than a PASI 50 response at week 24 or thereafter. W and R were 252. P < 0Æ001). during which patients were retreated with adalimumab (40 mg eow starting at week 1R. Here we describe the efﬁcacy and safety outcomes for patients in M03-658 who withdrew and restarted therapy. Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 164. PGA. Canada and Europe (NCT00195676). At the end of Period O. and all patients provided written informed consent before any study-related procedures were Fig 1. performed. every other week. M04-716 (CHAMPION)]. M03-656. pp434–441 . respectively (Fig. patients who had a Psoriasis Area and Severity Index (PASI) 75 response relative to baseline were rerandomized to receive either continuous adalimumab therapy or placebo for an additional 19 weeks (REVEAL Randomized Withdrawal Period). M02-538 ⁄ M03-596. baseline demographics. aAny patient who completed the study or discontinued early had a 70-day follow-up call. patients were administered open-label adalimumab 40 mg every other week (eow) as a single subcutaneous (SC) injection. and restarted on therapy. patients were withdrawn from therapy. 5%. suggesting that continuous therapy is necessary to maintain a high level of clinical response. mITT. after an 80-mg initial dose at week 0R) Patients with PGA scores of 0 or 1 at the last two study visits in Period O while receiving eow therapy Patients with stable psoriasis control at the end of Period O who entered Period W Patients in the mITT-W population who entered Period R eow.Retreatment with adalimumab for psoriasis. focusing on the patient population with stable control of their psoriasis prior to interruption of therapy. 40 and 16 weeks. The study consisted of three treatment periods: the open-label period (Period O).
Duration of adalimumab therapy prior to entering M03-658 ranged from 0 weeks (for patients who entered after having received placebo in REVEAL or CHAMPION) to 60 weeks (for patients who entered after completing M02-528 ⁄ 529).9 Serum adalimumab data were summarized by relapse status in Period W for the mITT-R population. Abnormal laboratory values that led to study withdrawal were considered adverse events. Pharmacokinetic and immunogenicity assessments Samples were drawn for the determination of serum adalimumab concentrations once at the beginning of the withdrawal period (week 0W). Patients with missing PASI or missing PGA were classiﬁed as treatment failures. 57% (347 patients) had stable psoriasis control in Period O. PASI is a measure of the severity and lesional characteristics of chronic plaque psoriasis. Serum adalimumab and antiadalimumab antibody (AAA) samples were analysed using a validated. Papp et al. K. speciﬁc and sensitive enzymelinked immunosorbent assay double-antigen technique described previously. mITT patients who entered Period W were deﬁned as the mITT-W population. or their response was between PASI 50 and 75 at week 33. including 62 with stable psoriasis control.6 The PGA is a static assessment of overall psoriasis severity (plaque elevation. mITT-W and mITT-R analysis populations are deﬁned in Table 1. AAA data were summarized as a frequency of AAA-positive (AAA+) samples at each visit. 2). Efﬁcacy and safety evaluations were performed at 12-week intervals in Period O (except for a visit 6 weeks after dose escalation for those patients who underwent dose escalation) and at 4-week intervals in Period W and Period R. 1047 of 1468) entered from the preceding phase III study REVEAL (Fig. Efﬁcacy assessments PASI and PGA of psoriasis severity were performed by the physician at the time of patient evaluation. symptom-speciﬁc scale whose score can range from maximal fatigue (0) to no fatigue (52). 0R. The primary efﬁcacy analysis for this population was the percentage of patients who achieved a PGA of ‘Clear’ (0) or ‘Minimal’ (1) at week 16R. pp434–441 . A total of 525 patients from Period W entered Period R. Samples for the evaluation of immunogenic- ity were drawn at weeks 0W. Of patients who entered from REVEAL. 227 had been PASI 75 responders at week 33 of REVEAL and had been withdrawn from therapy for up to 19 weeks during the REVEAL Randomized Withdrawal Period and 233 patients had been PASI 75 responders at week 33 of REVEAL and had been randomized to adalimumab therapy during the REVEAL Randomized Withdrawal Period. 1).436 Retreatment with adalimumab for psoriasis. laboratory evaluations. Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 164. 12R and 16R. induration and scaliness of lesions. with 0 indicating no psoriasis and greater scores indicating more severe disease. AAA+ patients were considered those who had at least one AAA+ sample during Period R (including week 0R) for further analysis by relapse status in Period W and responder status at week 16R for the mITT-R population. A total of 83 patients from Period W. The majority of patients (71%. Figure 3 shows the patient disposition for the alladalimumab treatment population during M03-658. all remaining (nonrelapsed) patients were entered into Period R. The mITT. Patients with stable psoriasis control (PGA scores of 0 or 1 at the last two study visits in Period O while receiving eow dosing) were the prespeciﬁed population of interest and were identiﬁed as the modiﬁed intention-to-treat (mITT) population. A total of 608 patients from Period O entered Period W. patients were monitored every 4 weeks for relapse (PGA ‡ 3). All adverse events were collected during the study and up to 70 days after the last dose of study drug or 70 days after study discontinuation. The FACIT-F scale is a 13-item. During Period W. During Period R. and during the retreatment period at weeks 4R. scaling and erythema) on a six-point scale ranging from 0 to 5. At week 40 of Period W.7 The Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) scores were also collected in Periods W and R. withdrawn from therapy and entered Period W. and those who received at least one dose of study medication in Period R were deﬁned as the mITT-R population. The most common primary reasons for premature discontinuation from Period O were unsatisfactory therapeutic effect (13%) and withdrawal of consent (10%). 12R and 16R. chest X-rays and electrocardiograms. Most of the remaining 587 patients who entered from REVEAL had less than a PASI 75 response at week 16. as well as the extent of erythema. patients were administered an 80-mg initial dose at week 0R and then received 40 mg eow at weeks 1R to 15R administered as single SC injections. of whom 285 had stable psoriasis control in Period O (178 entered after having relapsed in Period W. whereupon they entered Period R. did not enter Period R.8 Safety assessments Safety evaluations were conducted through patient histories and physical examinations including vital signs. Of these. More than half (59%) of patients in the all-adalimumab treatment population completed Period O. Results Patient disposition The all-adalimumab treatment population comprised 1468 patients who received at least one dose of adalimumab in M03-658 (Fig. Statistical analysis Efﬁcacy and safety were summarized for the mITT-R population. at the end of the withdrawal period (week 0R). It has a composite score ranging from 0Æ0 to 72Æ0 that comprises the degree of body surface area affected by psoriasis.
Reasons for exit from Period W reﬂect the primary reason for exit. . For patients with stable psoriasis control who did not relapse during Period W. At entry into Period R. 107 entered without having relapsed in Period W). Mean PASI scores were 7Æ3 for patients who had relapsed and 2Æ9 for those who had not relapsed. Distribution of patients from preceding phase II and phase III studies: patients who received at least one adalimumab injection in study M03-658. 437 Fig 2. the demographic and disease characteristics typically observed in a patient population with moderate to severe plaque psoriasis (Table 2). Comparative Study of HUMIRA vs. at the baseline of their preceding phase II or phase III studies. modiﬁed intention-to-treat. 96% (171 of 178) of those who had relapsed had a PGA of ‘Moderate’. Patient disposition for the all-adalimumab treatment population. K. whereas of those who had not relapsed 60% (64 of 107) had a PGA of ‘Clear’ or ‘MiniÓ 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 164. Papp et al. Methotrexate vs Placebo In PsOriasis PatieNts. Reasons for discontinuation in Periods O and R reﬂect the primary reason for discontinuation. bPatients were eligible to enter Period R upon experiencing a PGA ‡ 3. mITT. aPatients with a stable Physician’s Global Assessment (PGA) 0 or 1 response in Period O. Baseline demographics and clinical characteristics The mITT-W and mITT-R populations had. Sixteen of the 285 patients in the mITT-R population discontinued from the study. No patients in the mITT–W population experienced rebound during Period W. Psoriasis Area and Severity Index and Physician’s Global Assessment Median time to relapse for the mITT-W population was 141 days (interquartile range 93–202 days). CHAMPION.Retreatment with adalimumab for psoriasis. cAll patients in Period W who had not relapsed by week 40 entered Period R for retreatment with adalimumab. pp434–441 mal’ and 40% (43 of 107) had a PGA of ‘Mild’. median time between end of Period O and beginning of Period R was also 141 days. Fig 3. Randomized Controlled EValuation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis TriAL. REVEAL.
BSA. Psoriasis Area and Severity Index. n (%) Diagnosed Not diagnosed or missing a Period R mITT (n = 285) 213 (74Æ7) 265 (93Æ0) 46Æ0 ± 12Æ77 89Æ1 ± 20Æ93 87Æ0 (44Æ0–203Æ6) 17Æ9 ± 6Æ88 16Æ1 (6Æ0–52Æ9) 25Æ1 ± 15Æ70 20Æ0 (5Æ0–90Æ0) 5Æ7 ± 4Æ22 4Æ7 (0Æ0–25Æ5) 0 0 0 145 (58Æ9) 91 (37Æ0) 10 (4Æ1) 39 19Æ8 ± 11Æ77 18Æ5 (0Æ6–57Æ9) 74 (26Æ0) 211 (74Æ0) 256 (73Æ8) 322 (92Æ8) 46Æ0 ± 12Æ69 88Æ7 ± 20Æ75 86Æ0 (44Æ0–203Æ6) 17Æ7 ± 6Æ56 16Æ0 (6Æ0–52Æ9) 24Æ9 ± 15Æ34 20Æ0 (5Æ0–90Æ0) 0Æ7 ± 0Æ94 0Æ0 (0Æ0–4Æ8) 0 0 0 173 (57Æ9) 116 (38Æ8) 10 (3Æ3) 48 20Æ0 ± 11Æ95 18Æ6 (0Æ6–57Æ9) 90 (25Æ9) 257 (74Æ1) At baseline. The PASI 75 Fig 4. W ⁄ R)b Mean ± SD Median (range) PGA. PASI 75 ⁄ 90 ⁄ 100 response rates for patients in the mITT-R group were 87% ⁄ 64% ⁄ 34%. Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 164. last evaluation prior to the ﬁrst study drug administration (placebo. Study M02-528 used the seven-point PGA. Percentages calculated based on nonmissing values. Period R modiﬁed intention-to-treat. 76% of patients had a PGA response of ‘Clear’ or ‘Minimal’ at week 16R. At week 16R. mean ± SD Weight. K. or adalimumab) in studies M02-528. At week 16R. n (%) White.c n (%) ‘Clear’ (0) ‘Minimal’ (1) ‘Mild’ (2) ‘Moderate’ (3) ‘Severe’ (4) ‘Very severe’ (5) No data Duration of psoriasis. ‘Minimal’ or ‘Mild’. bLast evaluation prior to the start of Period W or Period R for the populations in Period W and R. 63%). Table 2 Demographic characteristics and baseline disease characteristics: Period W and Period R modiﬁed intention-to-treat (mITT) populations Period W mITT (n = 347) Male. cSix-point Physician’s Global Assessment (PGA) evaluations at baseline are summarized. For patients who had not relapsed. the PGA ‘Clear’ or ‘Minimal’ rate for the subsets who had relapsed during Period W (n = 178) was 69% (Fig. kg Mean ± SD Median (range) PASIa Mean ± SD Median (range) BSA with psoriasis. see Supporting Information). pp434–441 . body surface area. 4). mITT-R. In the mITT-R group.438 Retreatment with adalimumab for psoriasis. M03-656 or M04-716. Those patients in the mITT-R group for whom relapse occurred later (after the median time to relapse) were more likely to reachieve a PGA of ‘Clear’ or ‘Minimal’ at week 16R compared with those for whom relapse occurred before the median time to relapse (76% vs. these data were not included. compared with 93% for those who did not relapse. Papp et al.a years Mean ± SD Median (range) Psoriatic arthritis status. respectively. response rate for patients in the mITT-R group who relapsed was 83%. methotrexate. respectively (Table S1. 80%)].a % Mean ± SD Median (range) PASI (baseline. therefore.a. PASI. and 87% had a PGA response of ‘Clear’. Percentages of patients achieving a Physician’s Global Assessment (PGA) of ‘Clear’ or ‘Minimal’ during Period R. n (%) Age (years). M02-538. Patients in the mITT-R group who did not relapse and were restarted later (after the median time off therapy) were more likely to have a PGA of ‘Clear’ or ‘Minimal’ at week 16R compared with those who were restarted earlier [before the median time off therapy (98% vs. 89% had a PGA of ‘Clear’ or ‘Minimal’ at week 16R.
Three patients did not have AAA+ samples at week 0R but had AAA+ samples at weeks 12R (n = 1) or 16R (n = 2). the mean FACIT-F score was lower (fatigue was worse) for patients who had relapsed in Period W (40Æ8) compared with those who had not relapsed in Period W (43Æ9). including two serious infections: coronary artery disease. pp434–441 Fig 5. tendon rupture. Patients in the latter group represent patients who were treated in an otherwise identical fashion. there were no mITT-R patients with AAA+ samples (0 of 272). Prior to withdrawal of treatment at week 0W. fracture of humerus. Functional Assessment of Chronic Illness Therapy–Fatigue Prior to adalimumab withdrawal at week 0W. Papp et al. The percentage of AAA+ mITT-R patients who relapsed (7%. 12R and 16R. 133 (47%) experienced at least one adverse event during Period R. respectively). mean serum adalimumab concentrations were similar to those that were observed prior to withdrawal regardless of relapse status. Nine patients (3%) had serious adverse events during Period R. 4% (5 of 119) were AAA+ compared with 15% (8 of 55) of patients who relapsed in Period W and did not regain a PGA of ‘Clear’ or ‘Minimal’ at week 16R. Of the mITT-R patients who relapsed in Period W and regained a PGA of ‘Clear’ or ‘Minimal’ at week 16R. Patients in the former group represent those who were withdrawn from adalimumab twice (Period C of REVEAL and Period W of M03-658). 73% of patients who had been withdrawn from adalimumab twice had a PGA of ‘Clear’ or ‘Minimal’ compared with 63% for patients who had been withdrawn from adalimumab once. 7 of 106). From week 4R to week 16R. Figure 6 depicts the percentages of mITT-R patients with AAA+ samples at weeks 0W. 6% (17 of 275) of patients had AAA+ samples. PGA and PASI response rates at week 16R by AAA status for the mITT-R patients who relapsed in Period W are provided in Table S2 (see Supporting Information). except that they were withdrawn from adalimumab once (Period W of study M03-658). nephrolithiasis. Percentage of antiadalimumab antibody-positive (AAA+) samples by study visit: Period R modiﬁed intention-to-treat (mITT-R) population (nonmissing samples). 439 Included in the 178 mITT-R patients who relapsed were subsets of 37 patients who had been rerandomized to placebo and 43 patients who had been rerandomized to adalimumab in the REVEAL Randomized Withdrawal Period. respectively. mean serum adalimumab concentrations plateaued. abdominal adhesions and umbilical hernia. Mean ± SD serum adalimumab concentrations: Period R modiﬁed intention-to-treat (mITT-R) population. which is clinically relevant per the minimum clinically important difference of ‡ 3 points. K. Fig 6. At week 0R.Retreatment with adalimumab for psoriasis. chest discomfort. Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 164. achieving a PASI 75 response at weeks 16 and 33 as required by protocol. At week 16R. The mean change (worsening) in FACIT-F score from weeks 0W to 0R for patients who relapsed was –3Æ7 points. malignant melanoma in situ. pharmacokinetic and AAA samples were available for at least one time point for 280 patients. the percentages of patients with AAA+ samples decreased to 1% (3 of 264) and 2% (4 of 262). After retreatment at week 12R and week 16R. These two groups of patients from REVEAL responded well to adalimumab.10. 13 of 174) was similar to the percentage of AAA+ mITT-R patients who did not relapse (7%. pneumonia. After 4 weeks of retreatment with adalimumab. 0R. Pharmacokinetics and antiadalimumab antibodies In the mITT-R population. After withdrawal of treatment and just prior to retreatment at week 0R. Seventy-three (26%) patients . respectively). the mean FACIT-F score was 44Æ8 for patients with stable psoriasis control (44Æ4 and 45Æ5 for patients who did or did not undergo relapse.11 Relapsers in Period W experienced a signiﬁcant and clinically meaningful FACIT-F improvement of 3Æ2 points during Period R. Safety Of the 285 patients in the mITT-R group. Figure 5 depicts the mean serum adalimumab concentration for patients by relapse status in Period W over the ﬁve visits. and hepatitis C. and mean FACIT-F scores at week 16R were similar for patients who had relapsed in Period W compared with those who had not relapsed in Period W (44Æ1 and 44Æ4.
patients who received an initial 80-mg dose in Period R before resuming 40-mg eow dosing had better outcomes than what has been observed for patients who resumed adalimumab without an initial 80-mg dose. K. One injection-site reaction (in a patient who was AAA-negative) was reported. under contract with Abbott. however. lupus-like syndrome or allergic reactions were noted. Medical writing support was provided by Deborah Roney. and we found that 73% of patients who underwent two treatment interruptions achieved a PGA of ‘Clear’ or ‘Minimal’ following treatment with adalimumab for a third time. Discussion The results described here suggest that for patients with psoriasis who choose or need to undergo a treatment interruption with adalimumab. Adalimumab has the ﬂexibility to be used continuously or with treatment interruptions. In addition. there is a high likelihood that resumption of treatment will be efﬁcacious. Upon resumption of adalimumab. Carter of Arbor Communications and was funded by Abbott. Br J Dermatol 2010. What’s already known about this topic? • Antitumour necrosis factor agents are effective for treating moderate to severe plaque psoriasis. Gu Y et al. These results are consistent with previous reports that patients who relapse or discontinue and then restart adalimumab have a great likelihood of recapturing a high level of efﬁcacy. For patients with stable psoriasis control on adalimumab 40 mg eow. In the event that a physician and patient interrupt therapy. Additionally. continuous therapy cannot be made because the study design did not include a comparison group of patients who received continuous therapy. demyelinating disease. Optimal treatment strategies and the beneﬁt–risk of continuous therapy vs. The beneﬁt–risk proﬁle of retreatment with adalimumab following treatment interruption has not been characterized fully.12. these results provide some useful guidance regarding how best to execute this strategy. the risk of immunogenicity after withdrawal and 16 weeks of retreatment was low (2%). the results from this study reinforce that adalimumab is an effective agent for treatment of moderate to severe psoriasis with a favourable beneﬁt–risk balance. 162:1349–58. deﬁnitive conclusions regarding the beneﬁt–risk proﬁle of treatment interruption vs. and that most patients who do not regain a PGA of ‘Clear’ or ‘Minimal’ do not have AAAs. The prevalence of antiadalimumab antibodies following retreatment was low and was not associated with an increased risk of hypersensitivity reactions. which indicates that reappearance of symptoms of fatigue may be a signal that therapy should be reinitiated. Strober BE.14 The present work conﬁrms that the presence of AAAs is associated with an increased risk of failure to reachieve efﬁcacy following treatment discontinuation and relapse. and by characterizing the pharmacokinetics and immunogenicity for patients whose therapy was interrupted. In conclusion. Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 164. interruption of adalimumab was associated with a clinically relevant worsening of fatigue. Limitations of this study include its open-label study design and that patients were not required to revert to their original disease state to be considered relapsers. Patients who were retreated prior to relapse had better outcomes than patients retreated after relapse. experienced an infectious adverse event.440 Retreatment with adalimumab for psoriasis. congestive heart failure. most patients who relapsed were able to regain a clinically satisfactory level of response (69% reachieved a PGA of ‘Clear’ or ‘Minimal’) along with reduced fatigue. There is no evidence that AAA+ patients have a worse safety proﬁle compared with AAA-negative patients. Pharmacokinetic evaluations indicated that mean serum adalimumab concentrations were similar for patients before withdrawal compared with after 16 weeks of retreatment. We found that patients who resumed treatment before they relapsed generally had better efﬁcacy outcomes than patients who resumed treatment after they had relapsed. by using the indicated 40-mg eow adalimumab dose for psoriasis during retreatment. Acknowledgments The authors thank Dr Susan Paulson and Rochelle Jurasz of Abbott Laboratories for assistance with the pharmacokinetic data and Yuzhen Wang of Abbott Laboratories for statistical analysis. Papp et al. References 1 Langley RG. pp434–441 . these results also demonstrate that a small percentage of patients develops AAAs following treatment discontinuation and relapse. withdrawal of adalimumab was associated with disease relapse (median time to relapse of 141 days).13 but the present analysis extends the prior results by examining retreatment in a larger number of patients. There is no evidence of a difference in the safety proﬁle for adalimumab when administered with a treatment interruption.12. implementing a treatment interruption are subjects of debate. What does this study add? • Retreatment with adalimumab is effective for patients who had achieved stable psoriasis control and then relapsed following treatment interruption. that some patients who are AAA+ are able to regain clinical response. Multiple treatment interruptions are likely in clinical practice. Loss of efﬁcacy observed in some patients on long-term adalimumab therapy is associated with the development of AAAs. Likewise. and Cathryn M.13 Further. nonmelanoma skin cancer. Beneﬁt–risk assessment of tumour necrosis factor antagonists in the treatment of psoriasis. No fatalities and no opportunistic infection. and worsening of fatigue when off therapy may be a signal that therapy should be restarted.
J Pain Symptom Manage 1997. Supporting Information Additional Supporting Information may be found in the online version of the article: Table S1. Webster K et al. pp434–441 . Ó 2011 The Authors BJD Ó 2011 British Association of Dermatologists 2011 164. randomized clinical trial. Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Tyring SK. Oral presentation at: 49th Meeting of the Dermatologic and Ophthalmologic Advisory Committee. 11 Cella D. 13 Menter A. Eton DT. 158:558– 66. 8 Yellen SB.):AB183. a fully human antitumor necrosis factor-alpha monoclonal antibody. Driessen RJ. 5 Gordon K. J Pain Symptom Manage 2002. Spuls PI et al. Clinical trial design in psoriasis. Stingl G. Furst DE et al. methotrexate vs. Health Qual Life Outcomes 2003. Bethesda. randomised controlled trial and open-label extension study. Br J Dermatol 2008. 146:127–32. Efﬁcacy and safety of adalimumab treatment in patients with moderate to severe psoriasis: a doubleblind. Moreland LW. controlled phase III trial. Table S2. PGA ‘Clear’ or ‘Minimal’ and PASI 75 ⁄ 90 ⁄ 100 response rates at week 16R by AAA status for patients who relapsed in period W: mITT-R population. 24:547–61. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. 4 Gordon K. Cella DF. Germany. Blum R. PASI data by relapse status: mITT-R population. Efﬁcacy and safety results from the randomized controlled comparative study of adalimumab vs. 7–11 October 2009. Efﬁcacy. 25:1700–21. 13:4–11. 6 Fredriksson T. Leonardi C et al. 58:106–15. Any queries (other than missing material) should be directed to the corresponding author for the article. Sasso E. Gordon K et al. applications. Dubertret L et al. Gordon K. Papp K et al. 12 Lebwohl M. The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: properties. and interpretation. Papp et al. Blum R. Pettersson U. 14 Lecluse LL. 20 March 1998. Severe psoriasis: oral therapy with a new retinoid. placebo in patients with psoriasis (CHAMPION). Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. MD. pharmacokinetic. Cella D. J Am Acad Dermatol 2006. 441 2 Menter A. J Am Acad Dermatol 2009. 9 Weisman MH. Combining anchor and distributionbased methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J Am Acad Dermatol 2008. Lai JS et al. Arch Dermatol 2010. 3 Saurat JH. Langley RG. Relationship between effectiveness of restarting adalimumab and degree of psoriasis activity after a period of discontinuation. Berlin.Retreatment with adalimumab for psoriasis. 1:79. CHAMPION Study Investigators. 13:63–74. Clin Ther 2003. in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. 60 (Suppl. 157:238–44. 7 Ko H-S. Yost K. Poster presentation P201 at the 18th Congress of the European Academy of Dermatology and Venereology. 10 Webster K. and safety assessment of adalimumab. Adalimumab therapy for moderate to severe psoriasis: a randomized. Psoriasis Forum 2007. Efﬁcacy and safety of a second adalimumab treatment cycle in psoriasis patients who relapsed after adalimumab discontinuation or dosage reduction. K. 55:598–606. Okun M. Gu Y. Dermatologica 1978.
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