Combination of adalimumab with traditional systemic antipsoriatic drugs – a report of 39 cases

Authors


Dr. med. Sandra Philipp, Klinik für Dermatologie, Venerologie und Allergologie, Charité–Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Tel.: +49-30-450-51-8099, Fax: +49-30-450-51-8908, E-mail: sandra.philipp@charite.de

Summary

Background: Monotherapy with TNF-α inhibitors does not always produce a sufficient response in psoriasis patients. Combinations of TNF-α antagonists such as adalimumab with systemic antipsoriatic therapies such as methotrexate are not approved for use in psoriasis, and the published data are scarce.

Patients and methods: The charts of 39 psoriasis patients from 6 dermatology departments were reviewed retrospectively. All patients were given adalimumbab with another systemic antipsoriatic drug.

Results: Combination therapy with methotrexate was most common (n = 32), followed by acitretin (n = 4) and cyclosporine (n = 3). Combination therapy with methotrexate lasted 10.8 ± 11.2 months (mean), with cyclosporine for 6.8 ± 3.3 months, and with acitretin 12.9 ± 12.4 months. Combinations were effective in the majority of patients: 30/39 (76.9 %) had a good (n = 9) or excellent (n = 21) response. Two patients had a moderate response and 7 patients had a poor response and were switched to another treatment. Overall, safety was very good. Eighteen patients experienced 24 adverse events; none was severe and/or required hospitalization. Of these, 10/24 adverse events were infections, most often infections of the upper respiratory tract (n = 5), bronchitis (n = 2), and influenza (n = 1).

Conclusions: Combinations of adalimumab with traditional systemic antipsoriatic treatments offer a promising method for managing severe or recalcitrant psoriasis. More data are needed to determine the long-term safety and efficacy of these combinations.

Introduction

Tumor necrosis factor (TNF) antagonists are well established in the treatment of moderate to severe psoriasis. Although therapies combining TNF antagonists and disease-modifying antirheumatic drugs (DMARDs) are approved for treatment and are commonly used in rheumatology for treating psoriatic arthritis, the data on combination therapies consisting of TNF antagonists and conventional systemic psoriatic drugs in dermatology are scarce. TNF antagonists are approved for use as monotherapy in the treatment of psoriasis. Yet everyday clinical practice shows that monotherapy is often inadequate for treating recalcitrant psoriasis. Thus combination therapies with TNF antagonists and conventional systemic antipsoriatic drugs could be useful. Case reports on psoriasis patients notwithstanding, there are no data on the parallel use of adalimumab (ADA) and conventional systemic antipsoriatic agents.

To investigate the use of combination therapies consisting of ADA and other conventional systemic drugs, our study addressed the following questions:

  • • Are systemic combination therapies with ADA being prescribed for dermatological reasons?
  • • If so, with which medications is it combined and at what point in time?
  • • Which patients are considered candidates for treatment?
  • • What is the experience on the safety, tolerability, and efficacy of these combinations?

Methods

Databases from 6 psoriasis centers in Germany were searched retrospectively for patients who had received combination therapy with ADA and conventional systemic antipsoriatic treatments. Only those patients were included in whom combination therapy was initiated due to psoriatic skin disease rather than psoriatic arthritis. Patients with psoriatic arthritis were not excluded as a rule, but the dermatological symptoms had to be main indication for combination therapy. We collected demographic and disease-specific data such as psoriasis type, duration of disease, prior therapies, comorbidities, as well as dosages and duration of combination therapies and their adverse effects.

Depending on the information available, the effectiveness of treatment of psoriasis vulgaris was based on either the PASI score (psoriasis area and severity index) or on the percentage of body surface area (BSA) involvement. In 6 patients with pustular psoriasis, palmoplantar pustular psoriasis, or psoriasis vulgaris with palmoplantar involvement, either the BSA or the physician global assessment (PGA) was used. The scale for the latter was 0–4 (very good, good, moderate, and poor).

The efficacy of combination therapy was evaluated as follows: reduction in the PASI score or BSA of at least 75 %: very good; a reduction of at least 50 %: good; a reduction of less than 50 % was considered moderate; and a reduction of less than 25 % or no improvement or worse were considered poor. A reduction in the PASI score to 0–1.5, a BSA of 0 % and a PGA of 0–1 were considered an excellent response, even if no baseline PASI score was available. If a 75 % reduction in the PASI score was achieved only with hospitalization, intensive local therapy and/or UV light therapy, the result was considered “good” or “moderate” at best. Due to the small number of patients in treatment sub-groups, and the range of treatment regimes, a descriptive analysis was performed.

Results

Epidemiology

Thirty-nine psoriasis patients were identified who were given combination therapy with ADA and traditional systemic antipsoriatic therapies. Thirty-two patients were given a combination of ADA and MTX, 4 were given acitretin, and 3 received cyclosporine A (CsA). Nineteen women and 20 men, on average 48 ± 13 years of age, were included in the study. Thirty-five patients had plaque psoriasis, 4 had pustular psoriasis (generalized form: n = 2; palmoplantar form: n = 2). The average disease history was 23 ± 14 years. Seventeen patients (44 %) also had psoriatic arthritis (Table 1).

Table 1.  Epidemiology, specific psoriasis forms, comorbidities, and previous systemic therapies. (PSA = psoriatic arthritis, NB = unknown, w = female, m = male, CsA = cyclosporine A, FSE = fumaric acid esters).
Patient no. Age (years) Sex History of disease (years) Clinical type of psoriasis PSA Comorbidities Prior therapies
 
157w36Plaque psoriasisNoHypertension, osteoporosis, arthritis, panic attacksMTX, CsA, UV light therapy
220w5Pustular psoriasis (body)NoDepressionCsA, FSE, UV light therapy
333m13Plaque psoriasisYesNoneMTX, CsA, UV light therapy
427w24Plaque psoriasisNoHypertension, depression, nicotine abuseMTX, FSE, CsA, UV light therapy, leflunomide
549w18Plaque psoriasis, palmoplantar + inverse lesionsYesHypertension, dyslipidemia, depression, nicotine abuse, migraines, epilepsyMTX, FSE, UV light therapy
650w7Plaque psoriasisYesObesityMTX, UV light therapy, leflunomide
766w47Plaque psoriasisYesDyslipidemia, nicotine abuse, hypothyroidism, chronic pain syndromeMTX, FSE, UV light therapy, acitretin, etanercept
859w19Plaque psoriasisYesObesity, hypertension, dyslipidemiaMTX, FSE, CsA, UV light therapy, leflunomide, etanercept
953w5Plaque psoriasisYesObesityMTX, CsA, UV light therapy
1058m12Plaque psoriasisYesDepression, fibromyalgiaUV light therapy
1144m5Plaque psoriasisYesType 2 diabetes, nicotine abuseMTX, FSE, CsA, UV light therapy, etanercept, leflunomide
1250w34Plaque psoriasisYesObesity, allergiesMTX, FSE, CsA, UV light therapy
1347w34Plaque psoriasisNoObesity, allergies, depression, diffuse goiterMTX, FSE, UV light therapy, acitretin, Infliximab, mycophenolate mofetil
1469w47Plaque psoriasisYesObesity, arthritisMTX, FSE, UV light therapy
1558m31Plaque psoriasisYesObesity, hypertension, CHD, dyslipidemia, lumbar spine syndromeUV light therapy
1641w31Plaque psoriasisYesDepression, nicotine abuse, CIN II, migrainesEfalizumab, etanercept, UV light therapy, FSE, MTX
1759m10Plaque psoriasisNoHypertension, allergic rhinitis, reflux esophagitis, tinnitus, prior apoplexyMTX, UV light therapy
1848mNBPlaque psoriasisNoHypertensionMTX, FSE, UVA therapy, acitretin, infliximab
1950m30Plaque psoriasisNoNoneMTX, FSE, CsA, infliximab
2044m28Plaque psoriasisYesNoneMTX, CsA, FSE, UV light therapy
2139w34Plaque psoriasisNoObesity, urticaria factitia, gastritis, depressionMTX, CsA, FSE, UV light therapy
2258wNBPsoriasis pustulosa palmoplantarisNoObesity, allergic rhinitis, allerg. asthma, nicotine abuse, osteoporosisMTX, UV light therapy, etanercept, leflunomide
2343m42Plaque psoriasisYesObesity, hypertensionMTX, CsA, FSE, etanercept
2435m29Plaque psoriasisNoNicotine abuseMTX, FSE, UV light therapy, efalizumab
2531m28Psoriasis guttataYesAllergic rhinitis, nicotine abuse, depressionMTX, FSE, etanercept, acitretin, UV light therapy
2647m20Plaque psoriasisNoLiver enzyme elevationFSE, UV light therapy, acitretin, efalizumab
2719w3Pustular psoriasis (body)NoNoneCsA
2828m15Plaque psoriasisYesNoneMTX, FSE, UV light therapy
29NBmNBPlaque psoriasisNoDyslipidemiaFSE, UV light therapy
3037w10Plaques psoriasis with pustular lesions (body)NoObesityFSE, UV light therapy
3155m32Plaque psoriasisNoObesity, allergic rhinitis, hepatic steatosis, arrhythmia, hypertensionCsA, MTX, FSE, acitretin, UV light therapy, Infliximab, efalizumab
3254mNBPlaque psoriasisNoelevated Liver enzymes ↑(γGT), nicotine abuse, hypertensionMTX, CsA, FSE, UV light therapy, efalizumab
3355mNBPlaque psoriasis + palmoplantar involvementNoHand eczema, hypertension, type 2 diabetesMTX, CsA, FSE, UV light therapy
3459m40Plaque psoriasisYesObesity, hypertension, type 2 diabetesMTX, UV light therapy, Infliximab, etanercept
3557m15Psoriasis pustulosa palmoplantarisNoUlcerative colitisFSE, MTX, retinoids, CsA, PUVA, efalizumab, etanercept, Infliximab
3664w52Plaque psoriasisNoHypothyroidism, arrhythmia, anosmia, non-melanoma skin cancer (NMSC)PUVA therapy, acitretin, MTX
3765w7Plaques-Psoriasis with pustular lesions (body)Noelevated Liver enzymes ↑(γGT),Acitretin, UV light therapy, FSE, CsA, MTX, etanercept
3838m7Plaque psoriasisNoAtopic dermatitisMTX, FSE, UV light therapy
3944w10Plaque psoriasisNoNBMTX, FSE, CsA, UV light therapy

Comorbidities and prior treatment

The majority of patients (33/39, 84.6 %) had at least one accompanying disease, 18 patients had 3 to 6 comorbidities (Table 1). Patients had received an average of 3.9 antipsoriatic therapies (phototherapy or systemic medications) before beginning combination therapy with ADA and a traditional systemic agent (Table 1). Nearly half of all patients had taken at least one further biological drug in the past (17/39; 43.6 %).

Reasons for combination therapy

The reasons given for attempting combination therapy were lack of efficacy of earlier methods (n = 24), disease severity (n = 14), the goal of suppressing antibody formation to adalimumab (n = 3), or briefly overlapping treatment methods (n = 2) while switching therapies (Figure 1). In some instances, the treatment decision was influenced by more than one of the above-named reasons. When combination therapy was used from the beginning, the decision was primarily based on high disease activity, and thus sequential introduction of combination therapy due to an inadequate response to monotherapy. Table 2 presents the reasons for individual treatment decisions.

Figure 1.

Reasons for choice of combination treatments with regard to the sequence of combination; use of adalimumab first (n = 16), direct combination (n = 17), or use of traditional medication first (n = 6). For some patients more than one reason was given.

Table 2.  Specific reasons for combination treatment of adalimumab (ADA) with traditional systemic antipsoriatic treatments in certain patients.
Patient no. Combination Specific reason/result
 
33ADA + acitretin, then ADA + alitretinoinLesions on the body responded well to ADA, but palmar lesions persisted. Chronic hand eczema was considered in differential diagnosis. Retinoids were chosen for combination therapy as they are used in both diseases. Combination therapy led to marked improvement of palmar skin changes. (Figure 3)
35ADA + acitretinAccompanying disease: ulcerative colitis. ADA therapy led to marked improvement of intestinal symptoms, but without adequate clearance of skin lesions. Given the good response of the intestinal symptoms to therapy, combination therapy was chosen rather than switching treatment. Due to palmoplantar involvement, acitretin was chosen for combination treatment. The patient responded well to combination therapy.
36ADA + acitretinHistory of numerous UVB light and PUVA therapies as well as multiple NMSC (non-melanoma skin cancer). The combination with acitretin was chosen for two reasons: first, due to disease severity and, second, due to a potential positive effect of acitretin on the incidence of NMSC in patients who had been previously treated with several PUVA cycles.
38ADA + CsAAccompanying atopic dermatitis. Given that cyclosporine A is used in psoriasis and atopic dermatitis, treatment was first with cyclosporine A. The psoriasis did not respond adequately and thus therapy was to switch to ADA. To prevent a rebound after stopping cyclosporine A, ADA was begun before stopping cyclosporine A. The therapy was switched successfully. Cyclosporine A was first reduced and then discontinued altogether.

In 16 patients, treatment with ADA was begun and the classic antipsoriatic medication later added in combination (MTX in 12 patients, acitretin in 3 patients, and CsA in one patient). Six patients were already on MTX (n = 4) or CsA (n = 2) when ADA was added. Seventeen patients began immediately with combination therapy (ADA plus MTX: n = 16; ADA plus acitretin: n = 1).

The number of previous treatments in the various combination groups was approximately the same and on average was between 3 and 4 (Table 1). Of the patients who were first treated with either the direct combination or with ADA, 41.2 % and 56.3 % had previously used at least one biological drug. However, only 16.7 % (1/6) of patients that began treatment with a traditional systemic antipsoriatic drug before starting ADA had previously used any biological drug.

Administration of combination therapies ( Table 3 )

Table 3.  List of combinations that have been used per patient. Dosage of adalimumab (ADA), combination partner and dosage (in case of MTX per week, for cyclosporine and retinoids daily) as well as duration of combination (in months) and topically therapy are given. (*only scalp, **twice weekly [proactive], ***as required on refractory plaques; bl.Th. = skincare, Polido. = Polidocanol, Salicyl. = Salicylic acid preparation, St.cl. = steroids and class, Vit-D = vitamin D analogues, KG = body weight).
Patient no. ADA ADA: Initial dose Combination Dosage (mg) Duration of combination therapy (months) Topical therapy during combination treatment (weeks)
 
140 mg every 2 weeksnoMTX/week15.01.75Salicyl. 5 % (1), St.Cl. II (1), Urea 5 % (5)
240 mg every 2 weeksnoMTX/week10.0–15.03Urea 5 % (3)
340 mg every 2 weeksyesMTX/week15.07Salicyl. 5 % (1), LCD 5 % (2), Urea 5 % (3), bl.Th. (1)
440 mg every 2 weeksnoMTX/week20.011Vit-D (3), bl.Th. (8)
540 mg every 2 weeksyesMTX/week7.51.5Salicyl. 5 % (1), LCD 5 % (2), Vit-D (3) & Urea 5 % (3)
640 mg every 2 weeksnoMTX/week15.012Urea 5 % (6), Polido. 5 % (1), bl.Th. (5)
740 mg every 2 weeksyesMTX/week7.51.5Vit-D (4), St.Cl. II (1), Urea 5 % (1)
840 mg every 2 weeksnoMTX/week10.02.5Vit-D (4), Urea 5 % (3), bl.Th. (3)
940 mg every 2 weeksnoMTX/week10.06.75Vit-D (3), Urea 5 % (3), bl.Th. (21)
1040 mg every 2 weeksnoMTX/week15.05Vit-D (3), Urea 5 % (3), bl.Th. (14)
1140 mg every 2 weeksyesMTX/week15.00.5Salicyl. 5 % (1), LCD 5 % (1) + Vit-D (2)
1240 mg every 2 weeksnoMTX/week20.010.75Salicyl. 5 % (1), Polido. 5 % (1), Vit-D (2), St.Cl. III (1), bl.Th. (38)
1340 mg every 2 weeksnoMTX/week7.58Vit-D (3), St.Cl. II (1), Urea 5 % (3), bl.Th. (1)
1440 mg every 2 weeks/every 12 daysyesMTX/week7.5–10.03.5Salicyl. 5 % (1), St.Cl. II (1), Urea 5 % (10), bl.Th. (2)
1540 mg every 2 weeksnoMTX/week15.08St.Cl. III (1), Vit-D (3), bl.Th. (28)
1640 mg initially weekly/every 10 days/every 2 weeksYesMTX/week7.59.5St.Cl. III (3), bl.Th. (35)
1740 mg every 2 weeksYesMTX/week7.511.5Vit-D (12), Tar-based shampoo (6), St.Cl IV (14)*, bl.Th. (14)
1840 mg every 2 weeksNoMTX/week3.75–7.514St.Cl. III (8), St.Cl. II (6), Vit-D (10), Vit-D + St.Cl. III*** (16), bl.Th. (16)
1940 mg every 2 weeksNoMTX/week5.0–7.527Vit-D + St.Cl. III (12)***, bl.Th. (96)
2040 mg every 2 weeks/every 3 weeksNoMTX/week5.040Vit-D (8), bl.Th. (152)
2140 mg every 2 weeksNoMTX/week15.0–20.09St.Cl. IV + gentamicin (1.5), later St.Cl.IV (1.5) again, St.Cl.III (4), LCD 5 %+Salicyl.5 % (8), bl.Th. (21)
2240 mg every 2 weeksNoMTX/week5.0–15.036Vit-D (116) + Salicyl. 5 % (36) + St.Cl. IV*** (92), St.Cl. II (8), Vit-D + St.Cl. III** (8), bl.Th. (12)
2340 mg every 2 weeksNoMTX/week10.0–15.013bl.Th. (52)
2440 mg every 2 weeksNoMTX/week7.5–10.015bl.Th. (60)
2540 mg every 2 weeks/weeklyNoMTX/week5.0 -15.018bl.Th. (14), St.Cl. III***(8), bl.Th. (50)
2640 mg every 2 weeksYesMTX/week7.5–10.043St.Cl. III*** (16), St.Cl. II (20), St.Cl. III (28),Vit-D + St.Cl. III (96)***, St.Cl. II**+ Vit-D (12)
2740 mg every 2 weeks/every 4 weeksNoMTX/week5.0–15.07St.Cl. III (4), St.Cl. II (5), bl.Th. (4), St.Cl. III (2), St.Cl. II (2), bl.Th. (11)
2840 mg every 2 weeksYesMTX/week10.0–15.03.25bl.Th. (13)
2940 mg every 2 weeksNoMTX/week5.0–10.08St.Cl. III*** (32)
3040 mg every 2 weeksYesMTX/week20.05bl.Th. (20)
3140 mg every 2 weeksYesMTX/week10.03Vit-D + St.Cl. III** (12) + Polido. (12)
3240 mg every 2 weeksYesMTX/week15.01Vit-D + St.Cl. III** (4)
3340 mg every 2 weeksYesAcitretin/day Alitretinoin/day20.0–30.028Salicyl. 5 % (13), St.Cl. III (22), LCD + Salicyl. 5 % (4), bl.Th. (73) [especially on hands] Salicyl. 5 % (10), St.Cl. III (2), Vit-D+ St.Cl. III (10), Tar-based shampoo (13), Vit-D (4), bl.Th. (73) [scalp]
3440 mg every 2 weeksYesAcitretin per day25.02.5bl.Th. (20)
3540 mg every 10 daysNoAcitretin per day25.03St.Cl. III*** (12)
3640 mg weeklyNoAcitretin per day10.0–20.018bl.Th. (72)
3740 mg weeklyNoCsA per day100.0–150.0 [1.4–2.0 mg/kg KG]6St.Cl. IV (2), St.Cl. III*** (22)
3840 mg every 2 weeksNoCsA per day100.0–200.0 [1.3–2.5 mg/kg KG]10.5bl.Th. (42)
3940 mg every 2 weeksYesCsA per day200.0–250.0 [3.0–4.0 mg/kg KG]4Vit-D(6), Salicyl. 5 % (1), Urea 5 % (8),St.Cl.IV (1),

In most patients, ADA was administered at standard dosage of 40 mg (subcutaneous injection) every other week. Fifteen patients were given a “loading dose” of 80 mg (subcutaneous injection) or 40 mg (subcutaneous injection) followed by a 40 mg dose after one week. In 16 out of 24 patients the reason for deviating from the standard guidelines with regard to the initial dosage was concern about immunosuppression as a result of a direct combination with a traditional drug. The same reason was given for 6 additional patients, who were promptly switched from other systemic drugs, especially other TNF-α blockers, to ADA. In the remaining 2 patients, ADA was not yet approved for use against psoriasis vulgaris; the dosage was thus based on the rheumatologic dosage. In 6 patients higher doses were later prescribed and in 2 patients the intervals of administration were lengthened to 3 or 4 weeks.

Thirty-two patients were given a combination with MTX. The average dosage was 12.4 ± 4.5 mg with a median of 15 mg per week. Four patients received combination treatment with acitretin 10–30 mg daily, 3 with CsA 100–250 mg daily (1.3–4 mg/kg of body weight). The duration of combination therapy varied depending on the drug. For combination therapy with MTX, the drug was given for 10.8 ± 11.2 months (range: 0.5–43 months), CsA was given for 6.8 ± 3.3 months (range: 4–10.5 months), and acitretin for 12.9 ± 12.4 months (range: 2.5–28 months). Additional topical therapies are listed in Table 3.

Efficacy ( Tables 4–7 ) ( Figure 2 )

Table 4.  Psoriasis area severity index (PASI), body surface area (BSA), physician global assessment (PGA) for evaluation of efficacy with following classification in a 4 point scale (excellent, good, moderate, poor; #= not applicable as observation period or combination therapy already finished; x = no data).
Patient no. PASI baseline Efficacy 1–3 months Assessment Efficacy 4–6 months Assessment Efficacy 7–12 months Assessment Efficacy 13–36 months Assessment Total efficacy Comments
 
112.6PASI response 95 %Very good# # # Very goodWeek 7 PASI 0.6
315.9PASI response 94 %Very goodPASI response 100 %Very good# # Very goodWeek 6 PASI 1, Week 16 PASI 0
4×× × Week 40 PASI 7.2; Week 43 PASI 1.1Very good, with hospitalization# ModerateWeek 40 PASI 7.2; with hospitalization PASI 1,1, thus only moderate efficacy
536.2PASI response 85 %Very good# # # Very goodWeek 0 PASI 36.2, Week 6 PASI 5.4
6×× × Week 52 PASI 0Very good# Very goodWeek 48 PASI 0.1
712.6PASI response 100 %Very good# # # Very goodWeek 6 PASI 0
8×Week 10 PASI 1.9Very good, with hospitalization# # # GoodWeek 6 PASI 7.9, Week 10 PASI 1.9 with hospitalization, thus only good efficacy level
9×× Week 29 PASI 0Very good# # Very goodWeek 29 PASI 0, complete clearance
10×× Week 22 PASI 0Very good# # Very goodWeek 17 PASI 3.1 and Week 22 PASI 0
1110PASI response 92 %Very good, with hospitalization# # # Very goodWeek 0–2 with hospitalization; but prior to this, despite the use of 20 mg MTX and 3 weeks hospitalization. PASI was only reduced from 10.8 to 10.0, thus treatment was judged as very effective
12×× × Week 43 PASI 23.4Poor# PoorWeek 43 PASI 23.4, despite hospitalization Week 46 still PASI 10.5, thus poor efficacy
13×× × PASI 1.1Very good, with hospitalization# Good7 months: PASI 4.5, 8 months with hospitalization PASI 1.1, thus efficacy only good
1427.2PASI response 84 %With UV light therapy very goodPASI response 68 %Good# # GoodWeek 10 PASI 4.3 (with UV light therapy), week 14 PASI 8.8, but PASI reduction 68 %, thus good efficacy
15×× × Week 33 PASI 2.4Good, with hospitalization# ModerateWeek 30 PASI 8.3, Week 33 PASI 2.4, only moderate efficacy due to hospitalization
169.3× PASI response 65 %GoodPASI response 81 %Very good# Very goodWeek 18 PASI 3.3, Week 41 PASI 1.8
1714× PASI response 90 %GoodPASI response 91 %Good# Very goodPASI 14 at baseline, ADA + MTX after day clinic (PASI 4), Week 25 PASI 1.4, Week 50 PASI 1.3, good long-term efficacy, efficacy very good
1820× PASI response 64 %GoodPASI response 72 %Good# GoodWeek 25 PASI 7.3, Week 48 PASI 5.6
1914.2× PASI response 100 %Very good× PASI response 83 %Very goodVery goodWeek 27 PASI 0, Week 115 PASI 2.4
208.5× PASI response 100 %Very good× PASI response 80 %Very goodVery goodWeek 30 PASI 0, Week 172 PASI 1,7
2112.8PASI response 80 %Very goodPASI response 32 %ModeratePASI response 37.5 %Moderate# PoorGiven that after week 19 PASI 8.8 and Week 29 PASI 8, efficacy considered poor
2310× PASI response 81 %Very good× PASI response 79 %Very goodVery goodWeek 30 PASI 1.9, Week 58 PASI 2.1
2413.2× × PASI response 96 %Very goodPASI response 100 %Very goodVery goodWeek 42 PASI 0.5, Week 52 PASI 0.5, Week 82 PASI 0
2527.6PASI response 45 %ModeratePASI response 45 %ModeratePASI response 75 %Very goodPASI response 88 %Very goodVery goodWeek 6 PASI 15.3, Week13 PASI 15.3, Week 53 PASI 6.9, Week 72 PASI 3.3, because efficacy only moderate at first, though very good after 1 year, thus considered good
26BSA 50 %BSA reduction 94 % but PASI > 5Good× × BSA reduction 94 %, but PASI > 5GoodGoodWeek 9 PASI 5.2 [BSA 3 %], Week 105 PASI 9 [BSA 5 %], Week 147: PASI 6,8 [BSA 3 %], Week 173 PASI 5.9
2838.3PASI response 74 %GoodPASI response 97 %Very good##  Very goodWeek 7 PASI 10.1, Week 13 PASI 1
2914.9× PASI response around 20 % worsePoorPASI response 14 %Poor  PoorAdditional psychological stress (burn-out)
3115.1PASI response 7.9 %Poor# #   PoorWeek 12 PASI 13.9
3216.4PASI response around 40 % worsePoor# # # PoorWeek 3 PASI 23.1, Week 6 PASI 27.8 (treatment discontinued)
33PGA 4Week 4 PGA 2GoodWeek 26 PGA 1Very goodWeek 52 PGA 0Very goodWeek 112 PGA 1 Week 120 PGA 0Very goodVery goodPalmoplantar involvement, thus PGA (PASI always under 1.8)
3412.5PASI response 36 %Moderate# # # PoorWeek 10 PASI 8, then switch of treatment, thus efficacy considered poor
36(38) 5.6PASI response around 75 % worsePoorPASI response around 34 % worsePoorPASI response 46–64 %GoodPASI response 52 %GoodGoodPASI 38 before ADA therapy, after flare-up combination: Week 10 PASI 9.8, Week 16 7.5, Week 32 PASI 2, Week 45 PASI 3, Week 63 PASI 2.7, Week 72 PASI 2.7, given long-term stabilization of extremely severe psoriasis, good efficacy
3810.9× PASI response 84 %Very goodPASI response 85 %Very good  Very goodWeek 18 PASI 1.8, Week 45 PASI 1.6
3930.2PASI response 73 %GoodPASI response 67 %Good# # GoodWeek 6 PASI 8.2, Week 19 PASI 10.1, interim exacerbation (Week 13–16), dosage reduction not possible
Table 5.  Psoriasis area severity index (PASI), body surface area (BSA), physician global assessment (PGA) in patients with pustular psoriasis (n = 6) for evaluation of efficacy with following classification on a 4-point scale (excellent, good, moderate, poor; #= not applicable as observation period or combination therapy already finished; x = no data; PPP = pustular palmoplantar psoriasis; PP = pustular psoriasis).
Patient no. PASI baseline Efficacy 1–3 months Assessment Efficacy 4–6 months Assessment Efficacy 7–12 months Assessment Efficacy 13–36 months Assessment Assessment of efficacy overall Comments
 
2×PGA 1Very good# # # Very goodPsoriasis cum pustulatione, thus BSA
22PGA 1× Week 26 PGA 0Very goodWeek 57 PGA 0Very goodWeek 157 PGA 0Very goodVery goodSevere palmoplantar pustular disease, despite MTX, in combi with etanercept good skin results, but recurrent infections thus switched to ADA + MTX: after 6 months symptom-free, good clinical appearance until year 3; PPP, thus PGA
27BSA 60 %BSA reduction 97 %Very goodBSA reduction 100 %Very good#   Very goodPP thus BSA; Week 3 BSA 20 %; Week 11 BSA 2 %; Week 23 and 28 BSA 0 %
30BSA 15 %× Week 20 BSA 0 %Very good# # Very goodPP thus BSA; despite MTX 20 mg pustular flare BSA 15 % before therapy, combination Week 20 BSA 0 %
35PGA 3PGA 1Good# # # GoodPPP thus PGA
377.6PASI response around 54 % worsePoorPASI response around 125 % worsePoor# # PoorPsoriasis cum pustulatione; Week 3 PASI 1.5; Week 6 PASI 3.6; Week 10 PASI 11.7, Week 14 PASI 17.1
Table 6.  Safety and efficacy of combination therapy with adalimumab. All documented adverse effects per patient are listed. The adverse events are separated with regard to infections and non-infectious adverse events. In the last column efficacy is listed on a 4-point scale (excellent, good, moderate, poor).
Patient Combination duration (months) Combination with + combination order Adverse effects Non-infectious side effects Infections Efficacy
 
MTX + ADA (with loading dose) and direct combination
110.5MTX + directNone00Very good
71.5MTX + directNone00Very good
51.5MTX + directNone00Very good
37MTX + directNone00Very good
MTX + ADA (without loading dose) and direct combination
11.75MTX + directBronchitis01Very good
138MTX + directNone00Good
158MTX + directNone00Moderate
1210.75MTX + directBronchitis01Poor
411MTX + directNone00Moderate
612MTX + directNone00Very good
2313MTX + directNone00Very good
2415MTX + directInfluence 41N101Very good
1927MTX + directNone00Very good
MTX + ADA (with loading dose) and administration of ADA first
321MTX + ADA firstElevated liver enzymes (gGT, AP)10Poor
143.5MTX + ADA firstNone00Good
169.5MTX + ADA firstNone00Very good
3110MTX + ADA firstUpper respiratory infection, increased liver enzymes11Poor
2643MTX + ADA firstDermatomycosis01Good
MTX + ADA (without loading dose) and administration of ADA first
82.5MTX + ADA firstNone00Good
105MTX + ADA firstNone00Very good
96.75MTX + ADA firstNone00Very good
298MTX + ADA firstSymptoms of depression10Poor
219MTX + ADA firstUpper respiratory infection, diarrhea11Poor
1814MTX + ADA firstAbdominal symptoms (MTX?), upper respiratory infection11Good
2518MTX + ADA firstNone00Good
MTX + ADA (with loading dose) and administration of traditional therapy first
283.25MTX + trad. firstElevated ?GT10Very good
1711.5MTX + trad. firstUpper respiratory infection01Very good
MTX + ADA (without loading dose) and administration of traditional therapy first
2040MTX + trad. firstNone00Very good
Retinoid + ADA (with loading dose) and ADA first
342.5Acitretin + ADA firstNone00Poor
3328Acitretin + ADA firstJoint pain; improvement after dosage reduction, increased triglycerides, mild upper respiratory infection21Very good
Retinoid + ADA (without loading dose) and direct combination
3618Acitretin + directNone00Good
CsA + ADA (with loading dose) and ADA first
394CsA + ADA firstFatigue10Good
CsA + ADA (without loading dose) and administration of traditional therapy first
3810.5CsA +trad. firstNone00Very good
Table 7.  Safety and efficacy of combination therapy with adalimumab in pustular disease (n = 6). All documented adverse events per patient are listed. The adverse events are separated with regard to infections and non-infectious adverse events. In the last column efficacy is listed on a 4-point scale (excellent, good, moderate, poor; *ADA loading dose, ^pustular palmoplantar psoriasis).
Patient Combination duration (months) Combination with + combination order Adverse effects Non-infectious side effects Infections Efficacy
 
MTX + ADA (without loading dose) and direct combination
23MTX + directAbdominal complaints, diarrhea20Very good
277MTX + directAlopecia10Very good
22^36MTX + directOral candida infection01Very good
MTX + ADA (with loading dose) and trad. first
305MTX + trad. firstNone00Very good
Retinoid + ADA (without loading dose) and ADA first
35^3Acitretin + ADA firstHeadache10Good
CsA + ADA (with loading dose) and traditional therapy first
376CsA + trad. firstIncreased liver enzymes10Poor
Figure 2.

Number of patients with a poor, moderate, good, or excellent response to combination treatment with ADA (with or without loading dose) shown by sequence of combinations and use of traditional systemic drug, represented by yellow (cyclosporine with ADA loading dose), light yellow (cyclosporine without ADA loading dose), red (retinoid with ADA loading dose), orange (retinoid without ADA loading dose), dark blue (MTX with ADA loading dose), and light blue (MTX without ADA loading dose) color bars.

Combination therapies were effective in the majority of patients. 30/39 (76.9 %) patients had either a good (n = 9) or very good (n = 21) response to treatment.

Two patients had only a moderate response and 7 patients had a poor response and were thus switched to other therapies. The best results were achieved with direct use of combination therapy as well as when ADA was later added (example: patient no. 17, Figure 3a, b). When ADA was later added, 5/6 (83.3 %) patients had a very good response. Of those who began directly with combination treatment, 14/17 (82.4 %) had a very good (n = 12) or good (n = 2) response. Additional systemic treatment after an inadequate response to monotherapy with ADA was effective in 11/16 patients (68.8 %). Of these, 4 patients had a very good response and 7 had a good response.

Figure 3.

Patient 17, back of lower limbs. (a) Multiple psoriatic lesions after monotherapy with MTX; (b) nearly complete clearance of lesions after 9 months of combination therapy with ADA and MTX.

Of the three patients who received combination therapy with ADA and CsA, tapering and then completely stopping CsA was successful in one patient (no. 38). Yet in another patient (no. 39), CsA could not be tapered; the combination was only effective at a dosage of CsA 4 mg/kg of body weight. In a third patient (no. 37), CsA was decreased due to elevated liver enzymes and later stopped due to lacking efficacy of combination therapy.

Of the 4 patients who were treated with retinoids in combination with ADA, 1 patient (no. 33) had a very good response, 2 had a good response (no. 35, no. 36), and only 1 patient (no. 34) had a poor response.

In 19/32 patients, combination therapy with MTX led to a very good response, in 6/32 a good response, in 2/32 a moderate response, and in 5/32 a poor response. In a few patients (n = 5), the MTX dosage as part of combination therapy could be decreased over the course of disease given a very good response or good response. In 2 patients (no. 2, no. 23) the dosage was reduced from 15 to 10 mg/weekly, and in patient no. 24 from 10 mg to 7.5 mg per week. In one patient (no. 28), the MTX dosage was tapered and the drug later stopped. Another patient (no. 19), in whom disease was stable, chose to reduce the MTX dosage from 7.5 to 5 mg/weekly.

Safety ( Table 6 , 7 )

Combination therapy was very safe overall. There were 24 adverse events in 18 patients, but none of these was severe and/or required hospitalization. 10/24 adverse events were infections, usually of the upper respiratory tract (n = 5), as well as bronchitis (n = 2) and influenza (n = 1). One patient was diagnosed with recurrent oral candidiasis and one patient with cutaneous mycosis. Non-infectious adverse events included abdominal complaints (n = 2, combination therapy with MTX), diarrhea (n = 2, combination therapy with MTX), and elevated liver enzymes (n = 4; 1 combination therapy with CsA and 3 with MTX).

In 6/18 patients, the adverse effects necessitated treatment modification. In 2 patients (no. 12, no. 17) ADA was stopped briefly as a result of infection. MTX dosage reduction from 7.5 mg to 5 mg alleviated gastrointestinal complaints in patient no. 18. In patient no. 22, recurrent oral candidiasis improved after reducing MTX to 5 mg/weekly, without any change in skin lesions. Patient no. 37 had elevated liver enzymes while taking CsA 2 mg/kg of body weight daily. The CsA dosage was initially reduced, later combination therapy had to be discontinued given its ineffectiveness. Patient no. 33 developed arthralgia and elevated triglyceride levels after 76 weeks of acitretin. The patient was switched to alitretinoin 30 mg/daily until week 120, which was reduced to 20 mg after arthralgia returned. The combination therapy continued to be effective (Figure 4a–c). Only in one patient (no. 36) combination therapy (ADA plus MTX) was stopped due to adverse effects. ADA was discontinued after 14 weeks due to recurrent infection.

Figure 4.

Patient no. 33. (a) Massive hyperkeratosis before treatment with ADA; (b) discrete hyperkeratosis and erosions after 8 months of combination use of ADA and acitretin; (c) complete clearance after 6 months of combination use of ADA and alitretinoin.

Discussion

When deciding whether to combine ADA with traditional systemic antipsoriatic drugs, the efficacy of combination therapy and potential adverse effects must be taken into consideration. In traditional systemic antipsoriatic therapies, the dosage and duration of treatment are frequently limited due to organ-specific toxicity (such as nephrotoxicity in CsA). Organ-specific toxicity is not as much of an issue with TNF antagonists, with the possible exception of certain diseases such as TNF antagonist-associated hepatitis. Thus an increased risk of organ-specific toxicity in combination therapy is generally not an issue. In addition, the response to combination therapies may be sufficient even after reducing the traditional systemic therapy dosage, thus enhancing tolerability [1]. The most serious adverse effects related to combination therapies are infections and cancer.

There is a wealth of experience concerning the use of MTX with biologicals in rheumatologic diseases. Results have been reported from prospective clinical studies as well as everyday practice. The use of TNF antagonists in combination with MTX is approved for use in a variety of rheumatologic disorders. Studies have shown that combining ADA with MTX can reduce the formation of anti-ADA antibodies which reduce its effectiveness [2, 3]. The early combination of MTX with ADA could thus prevent diminished efficacy in some patients. Our retrospective analysis revealed that prevention of anti-ADA antibodies was the reason in 3/32 patients for combination therapy with ADA and MTX. The combination of MTX with ADA was effective in 17/20 patients; treatment was either started with ADA and MTX simultaneously or ADA was added after MTX therapy had already begun. The efficacy was comparable to that of ADA, which is known to be effective. Thus one cannot judge the effect of MTX in the response to combination therapy. Yet in patients in whom the use of ADA alone did not adequately control symptoms, the addition of MTX led to a good or very good response (8/12 patients). Hence MTX may be considered for combination treatment of psoriasis in patients in whom the use of ADA alone is insufficient. In other studies with psoriasis patients who did not adequately respond to MTX, the long-term combination of etanercept with MTX was more effective than etanercept and MTX followed by a dosage reduction and discontinuation of MTX [4, 5].

In combination therapies with CsA and TNF-αntagonists, the biggest concern is a possibly increased risk of cancer. CsA appears to be associated with a higher incidence of malignancies [6], possibly due to its inhibiting effect on DNA repair and its ability to induce double-strand breaks [7, 8]. In a longitudinal, prospective cohort study, an increased incidence of malignant neoplasia was found in patients who had taken CsA, and a significant correlation was identified between the degree of risk and the duration of treatment (> 2 years) [9].

Although an association between TNF-αntagonist therapy and an overall increase in malignancy has not been shown with certainty, it cannot be ruled out. There is evidence, of an increased risk of non-melanocytic skin tumors in patients with rheumatoid arthritis who have been treated with TNF antagonists [10]. Thus it is conceivable that additive or synergistic effects of combination therapy with CsA and TNF antagonists could have an impact on the risk of cancer. To our knowledge there are no published data on combination therapy with CsA with ADA in psoriasis patients. There are case reports, case series, and open studies on patients with psoriasis and/or psoriatic arthritis who were given combination treatment consisting of etanercept and CsA, which was effective and which did not lead to serious adverse effects [11–14]. In our study, the average length of combination therapy with ADA and CsA was 6.8 months which is shorter than the combination of ADA and MTX or retinoids. As the data shown in Tables 6 and 7 demonstrate, there was no general relationship between longer use of combination therapy and an increase in side effects.

Still, until further data on the long-term safety of combination treatment with ADA and CsA are available, this measure should be reserved for use as rescue therapy or as a temporary measure (as was the case in two of the three patients presented here) or for the treatment of severe recalcitrant pustular psoriasis.

Acitretin is the only systemic antipsoriatic therapy that has no immunosuppressive effects. In the case series presented here, three out of four patients who received combination therapy with ADA and acitretin responded well or very well. In the literature there are two case reports on combination therapy with ADA and acitretin which also report favorably on tolerability and efficacy [15, 16]. In addition, a clinical study on etanercept 25 mg/weekly combined with acitretin 0.4 mg/kg of body weight daily found this to be just as effective as etanercept 2 × 25 mg/weekly and more effective than acitretin monotherapy; hence there is evidence for a good level of efficacy and tolerability of combination therapy with acitretin and a TNF antagonist [17]. A case-control study on retinoids and PUVA therapy showed that acitretin could reduce the risk of squamous cell carcinoma in patients treated with PUVA [18]. In addition to the increased efficacy of combination treatment with acitretin and ADA, the theoretical – although still unproven – possibility of a favorable effect of acitretin on the risk of skin cancer could influence the decision for combination therapy, as was the case in patient no. 38. Acitretin could also be a favored combination drug for ADA in the treatment of psoriasis patients with pustular lesions, given that acitretin is known to be effective in the treatment of pustular psoriasis.

Another traditional antipsoriatic agent, fumaric acid esters, are not described here nor are they found in the literature as combination partners for ADA or TNFa blockers. In our study, this may be due to the fact that the majority of patients had been treated in the past with fumaric acid esters and there was no incentive to try again.

In summary, combination therapy with ADA and traditional systemic antipsoriatic drugs is a treatment option for certain sub-groups of psoriasis patients. This includes patients who do not respond adequately to monotherapies, those with extremely severe psoriasis, and those with pustular or palmoplantar psoriasis. Combination therapy with MTX is also an option for reducing the risk of developing anti-ADA antibodies. In the case series presented here, combination therapy consisting of ADA and traditional systemic antipsoriatic therapies was well tolerated and, in most patients, was effective. No serious side effects were reported. The case series suggests that short-term treatment with ADA and acitretin, CsA, or MTX is well tolerated. For more exact and reliable results, a larger sample is needed, however. The brief duration of treatment significantly limits the conclusions that can be made on the safety of longer-term combination therapy. Other important limitations of this study are the small number of patients and its retrospective and uncontrolled design. Especially in patients with simultaneous administration of ADA and a traditional systemic antipsoriatic medication, it is impossible to clearly attribute the effects to one drug or the other. Data on combination therapies are to be expected from the analysis of information contained in psoriasis registries. In addition, there is a need for randomized, placebo-controlled clinical studies on the use of combination therapies in psoriasis.

Conflict of interest

Sandra Philipp received funding for her work on clinical studies, as well as lecture fees, compensation for advisory duties, and travel reimbursement from (in alphabetical order) Abbott GmbH & Co. KG, Actelion Pharmaceuticals GmbH, Biogen IDEC GmbH, Biotie Therapies, Essex Pharma GmbH, Galderma Laboratorium GmbH, Intendis GmbH, Isotechnika Pharma Inc., Janssen-Cilag GmbH, Merck Serono GmbH, Novartis Pharma GmbH, Pfizer GmbH, Revotar Biopharmaceuticals AG, Schering-Plough Corporation, UCB Pharma GmbH, and Wyeth Pharma GmbH.

Dagmar Wilsmann-Theis received funding for work on clinical studies, as well as lecture fees, compensation for advisory duties, and travel reimbursement from (in alphabetical order) Abbott GmbH, Almirall Hermal GmbH, Biogen IDEC GmbH, Essex Pharma GmbH, Galderma Laboratorium GmbH, Intendis GmbH, Janssen-Cilag GmbH, Leo Pharma GmbH, Merck Serono GmbH, Novartis Pharma GmbH, Pfizer GmbH, Schering-Plough Corporation, UCB Pharma GmbH, and Wyeth Pharma GmbH.

Ansgar Weyergraf received funding for work on clinical studies, as well as lecture fees, compensation for advisory duties, and travel reimbursement from (in alphabetical order) Abbott GmbH, Essex Pharma GmbH, Janssen-Cilag GmbH, Leo Pharma GmbH, and Wyeth Pharma GmbH.

Sebastian Rotterdam received funding for work on clinical studies, as well as lecture fees, compensation for advisory duties, and travel reimbursement from (in alphabetical order) Abbott GmbH & Co. KG, Almirall Hermal GmbH, Biogen IDEC GmbH, Essex Pharma GmbH, Intendis GmbH, Pfizer GmbH, and Wyeth Pharma GmbH.

Yvonne Frambach received funding for work on clinical studies, as well as lecture fees, compensation for advisory duties, and travel reimbursement from (in alphabetical order) Abbott GmbH & Co. KG, Almirall Hermal GmbH, Basilea Pharmaceutica Ltd., Cephalon GmbH, Essex Pharma GmbH, Galderma Laboratorium GmbH, Intendis GmbH, Isotechnika pharma inc., Janssen-Cilag GmbH, Leo Pharma GmbH, Merck Serono GmbH, Novartis Pharma GmbH, Pfizer GmbH, Photocure ASA, photonamic GmbH & Co. KG, Schering-Plough Corporation, and Wyeth Pharma GmbH.

Sascha Gerdes received funding for work on clinical studies, as well as lecture fees, compensation for advisory duties, and travel reimbursement from (in alphabetical order) Abbott GmbH & Co. KG, Biogen IDEC GmbH, Pfizer GmbH, MSD Sharp & Dohme GmbH, and Janssen-Cilag GmbH.

Rotraut Mössner received funding for work on clinical studies, as well as lecture fees, compensation for advisory duties, and travel reimbursement from (in alphabetical order) Abbott GmbH & Co. KG, Biogen IDEC GmbH, Essex Pharma GmbH, Janssen-Cilag GmbH, Leo Pharma GmbH, Merck Serono GmbH, Novartis Pharma GmbH, Pfizer GmbH, and Wyeth Pharma GmbH.

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