2013 January-March; 1(1): 15–18. ISSN: 2282-4103
Published online 2013 April 5.

Cyclosporine in the era of biologics: a mini-review with special emphasis on the possible use in combination with biologics for psoriasis

Nicoletta Cassano and Gino A. Vena

Unit of Dermatology and Venereology, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy

Address for correspondence: Gino A. Vena, MD, Dermatology Clinic, DIMO Department, University of Bari - Policlinico, Piazza Giulio Cesare, 11, 70124 Bari, Italy, Phone and Fax: +39 080 5478920, E-mail: ginoantonio.vena@uniba.it

Summary

Combination of systemic biological and traditional agents is increasingly used for the treatment of “high-need” patients with psoriasis. There are only limited data on the combination of cyclosporine with biological drugs for the treatment of psoriatic disease. This article briefly reviews the available information on this combination strategy.

Keywords: psoriasis, cyclosporine, anti-TNF treatment, biological drugs, combination therapy

Introduction

Combination therapy is an important strategy for the management of plaque psoriasis and is aimed at optimizing the effectiveness and tolerability of treatment. Combination of systemic biologic and non-biologic agents is increasingly considered for the treatment of “high-need” patients with moderate-to-severe psoriasis, especially in those with particularly severe and refractory disease (1, 2). In fact, data from recent European reports have indicated that biological therapy is given concomitantly with traditional systemic drugs in up to 30% of psoriasis patients (35).

The association of anti-tumor necrosis factor (TNF) drugs with disease-modifying antirheumatic drugs (DMARDs) is often taken into consideration in rheumatological practice, and, in particular, combination treatment with methotrexate (MTX) has been extensively studied and used in rheumatologic indications, especially rheumatoid arthritis (RA). More in detail, the use of MTX is strongly recommended for the treatment of RA with TNF blockers, particularly anti-TNF monoclonal antibodies, as this DMARD has proved to be capable of reducing the formation of anti-drug neutralizing antibodies and the clearance of biological drugs.

However, the use of immunosuppressive drugs in combination with biologics in psoriasis is generally not indicated; therefore, the risk/benefit ratio of this “off-label” approach should be cautiously considered. In psoriasis, in spite of the ever-growing importance of combination therapies in clinical practice, the literature contains very few data on the combination of biologics and conventional systemic drugs. Compared to MTX, even more limited information exists about the role of cyclosporine (CsA) as a part of the combination strategy.

This article briefly presents an overview on the use of oral CsA in combination with biologics in psoriatic disease, focusing the attention on anti-TNF drugs, as there are no data on ustekinumab, and adding a short mention to efalizumab, whose market authorization was discontinued in 2009. This review does not include biologic drugs which are available only in other countries (i.e., alefacept).

Methods

The PubMed (MEDLINE) and EMBASE databases were searched using the terms ‘psoriasis’, ‘combination’, ‘cyclosporin(e)’, ‘etanercept’, ‘infliximab’, ‘adalimumab’, and ‘efalizumab’. Searches were limited to clinical studies involving adults that were published in English. References were checked for additional sources. The most important information on experimental studies and rheumatological experience in RA and psoriatic arthritis (PsA) with anti-TNF agents and CsA was also added using the above-mentioned data sources.

Data synthesis

General data and use in RA patients
Possible synergistic effects of CsA and anti-TNF-alpha drugs were shown in experimental models (6). In particular, the activity of either the single drug or their combination was investigated in type II collagen-immunized DBA/1 mice with arthritis, comparing such treatments with a control consisting in saline. CsA improved arthritis and suppressed interferon (IFN)-gamma production by CD4+ T cells. CsA also reduced the expression of TNF-alpha in affected joints through the reduction in Th1 cell-mediated response while TNF-alpha production by macrophages was not directly affected by the drug. Anti-TNF-alpha therapy was found to diminish IFN-gamma production by T lymphocytes.

In an open-label study, multiple intravenous infusions of 3 mg/kg infliximab were given for 12 months in 18 patients with refractory RA receiving CsA (2 mg/kg/day) and prednisone (5 mg/day) (7). The combination treatment with CsA, prednisone and infliximab led to the achievement of the American College of Rheumatology (ACR) 20 response criteria in 80% of patients while the ACR 50 response rate was 39%. Overall tolerability was good in most patients; treatment withdrawal was required in two cases because of adverse reactions, represented by an acute hypersensitivity reaction and pulmonary tuberculosis, respectively. Based on this experience, authors’ opinion supported the possible role of CsA as alternative DMARD to be used in combination with infliximab in patients with refractory RA who are unresponsive or intolerant to MTX (7).

Open-label studies in small series of RA patients evaluated the addition of CsA to infliximab and MTX showing controversial results and overall minor evidence for convincing beneficial effects (810).

Isolated case reports documented the safety of combination therapy with CsA and TNF-alpha blockers (adalimumab and etanercept) in RA patients and concomitant HCV infection (11).

Use in psoriatic disease
There are an overall paucity of reports and a lack of general consensus regarding the use of conventional systemic drugs and biologics in psoriasis, despite the frequent use of such combination regimens in clinical practice. Very limited data are available on the use of CsA combined with biologics for psoriasis.

Some reports evaluated transition from CsA to biologics, such as etanercept or efalizumab, in patients requiring CsA discontinuation (1214). In such circumstances, especially in severe refractory cases, transient overlapping of biologic therapy and CsA can be considered, and CsA dose can be gradually tapered in order to prevent flare-up or rebound of cutaneous lesions.

CsA might be part of sequential treatment approach to psoriasis. For instance, CsA can be used in patients who need to discontinue biological therapy in order to avoid rebound or to maintain clinical response (14). In patients receiving intermittent treatment with etanercept, sequential use of cyclosporine might be useful in selected cases to postpone psoriasis relapse. Maintenance CsA low-dose schemes may be helpful for this purpose, including the “week-end” regimen (15).

Of note, the results of a small open-label pilot study indicated that treatment with only 2 infliximab infusions caused a striking improvement of psoriasis, which could be sustained in most cases by the sequential use of CsA 3 mg/kg/day over a 24-week period in patients who had previously failed to respond to CsA ≥3 mg/kg/day (16). These preliminary results appeared to suggest the possible hypothesis that infliximab can restore the clinical response to conventional treatments previously found as ineffective.

Combined treatment with etanercept and CsA has been successfully used to control generalized pustular psoriasis (17).

CsA has been administered as a rescue option, with or without interruption of biologic therapy, in patients experiencing transitory return of psoriasis lesions during biologic treatment or to manage severe exarcerbations of psoriasis, including erythrodermic or generalized pustular psoriasis or de novo appearance of psoriasis (14, 1822).

In a series of 7 patients with psoriasis poorly controlled by conventional treatments, induction therapy with etanercept 50 mg once weekly (QW) and CsA at the daily dosage of 200 mg caused a marked response of skin lesions after a range of 4 to 12 weeks (23). An improvement of the Psoriasis Area and Severity Index (PASI) of at least 50% (PASI 50) was observed in all subjects and 6 of them had also a PASI improvement of 75% or more (PASI 75). Response was then sustained during a subsequent maintenance treatment with CsA 100 mg/day and etanercept 25 mg twice weekly (BIW) for 16–64 weeks (23).

A retrospective analysis reviewed the results obtained with etanercept 50 mg QW and CsA, given at doses in the range 3–5 mg/kg BIW, with an interval of 3–4 days (24). This retrospective study involved 17 patients who required the combination therapy for different reasons: primary inefficacy (n= 4) or secondary inefficacy (reduction of drug efficacy in patients who were previously responders) of etanercept monotherapy (n= 3); persistence of disabling cutaneous lesions at critical sites, despite a significant improvement in the general PASI score (n= 5); flare of psoriasis during etanercept treatment after interruption of efalizumab therapy (n= 5). Patients with concomitant PsA in the case series had PsA symptoms well controlled by etanercept monotherapy. The addition of CsA was capable of inducing a relevant clinical benefit on skin lesions in a total of 12 patients. The combination treatment was well tolerated. Only a patient experienced relevant side effects (repeated hypertensive crises) which caused CsA discontinuation after 2 months.

Very interesting data exist about the use of CsA in association with TNF-alpha inhibitors in PsA (2527).

A pilot study evaluated 11 PsA patients treated with etanercept 50 mg QW for at least 24 weeks who obtained remission of their PsA with unsatisfactory response of skin lesions (defined by a PASI score of at least 10 despite biological therapy) (25). In such patients the addition of CsA, at a daily dose of 3 mg/kg, to etanercept 50 mg QW was well tolerated and led to the achievement of the PASI 75 in 9 patients after 24 weeks.

In another pilot study, 41 PsA patients were randomized to receive etanercept 50 mg QW in association with CsA (3 mg/kg/day) or etanercept 50 mg QW in combination with MTX (7.5–15 mg/week) for 6 months (26). The two combination regimens were equally effective on PsA symptoms and did not show relevant differences in the rate of adverse events, except for hypertension which was more frequent among CsA-treated patients. Of note, etanercept plus CsA proved to be more efficacious than etanercept plus MTX in controlling skin lesions, with the former regimen being associated with PASI 50 and PASI 75 responses at 6 months in 88% and 53% of cases versus 73% and 32% of patients treated with etanercept and MTX.

There are only anecdotal reports on combination therapy with adalimumab and CsA for psoriasis, that documented mixed efficacy results (28).

Interesting considerations can be drawn by the results of a prospective 12-month open-label trial, evaluating the combination of adalimumab and CsA in patients with severely active PsA and inadequate response to MTX (27). The combined therapy proved to be safe and seemed to produce an overall major clinical improvement. In this trial, 57, 58, and 55 patients were treated with CsA (2.5–3.75 mg/kg/day), adalimumab (40 mg every other week), or combination of both drugs, respectively. At 12 months, the Psoriatic Arthritis Response Criteria were obtained by 65% of patients who received CsA alone (p=0.0003 in favor of combination treatment), 85% of adalimumab-treated patients (p=0.15 vs combination treatment), and 95% of patients treated with the combination, while the ACR 50 response rates were 36%, 69%, and 87%, respectively (p<0.0001 and p=0.03 in favor of combination treatment). A significantly greater mean improvement in Health Assessment Questionnaire Disability Index was achieved by combination treatment as compared to CsA or adalimumab alone. In 119 patients who had at least 2.5% of body surface area affected by psoriatic plaques at baseline, all three treatment modalities caused a significant improvement of psoriasis throughout the entire study period. At 6 months, the PASI 50 and PASI 75 response rates were 55% and 25% for the CsA group, 44% and 23% for the adalimumab group and 71% and 37% for the combination group. At the end of the study, 84.1% and 68.2% of patients who received combination treatment reached the PASI 50 and PASI 75, respectively. Notably, at 12 months, combination therapy significantly improved psoriasis beyond adalimumab, but not beyond the effect of CsA monotherapy.

Conclusions

Limited data are available on the use of CsA in combination with biologics for psoriatic disease. The few available data seem to suggest the safe and effective use of CsA in combination with anti-TNF biologics in psoriatic disease. This combination strategy might be used in selected cases for short periods of time, i.e. as a rescue therapy aimed at potentiating or restoring clinical response to anti-TNF drugs, before considering switch to an alternative biologic drug (29).

Despite these encouraging data, it has to be highlighted that the use of immunosuppressive drugs is not indicated in combination with biologics in psoriasis, and therefore a careful assessment of the risk/benefit ratio should be recommended and be individually considered. The possible synergistic effects of the combination also imply the enhancement of immunosuppression, with potential risk of deleterious effects particularly with high dosages and prolonged treatment periods. Most of the published reports concerned the association of CsA with etanercept, possibly because of the peculiar mode of action and the less immunosuppressive activity of etanercept compared to anti-TNF antibodies (30).

The combination of CsA and biologics warrants further investigation in psoriatic disease, as well in other inflammatory immune-mediated conditions.

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