L. Kircik, MD
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
Hand and foot psoriasis is a chronic and debilitating disease that manifests as plaque-type or pustular-type lesions. Although the palms and soles represent only 2% of the total body surface area, psoriasis of these regions may lead to physical dysfunctions that can greatly impair dexterity, mobility, and the quality of life of affected individuals. Deregulation of T-lymphocyte-mediated immune response is important in the pathophysiology of psoriasis. Efalizumab (Raptiva®, Genentech) is an anti-CD11a monoclonal antibody that disrupts the interaction between T cells and antigen-presenting cells, thereby inhibiting various T-cell-mediated immune processes that include activation and trafficking. Recent evidence indicates that efalizumab may be beneficial for patients with hand and foot psoriasis.
Hand and foot, psoriasis, efalizumab, monoclonal antibody
Pathophysiology and Prevalence
Psoriasis is a chronic, inflammatory, autoimmune skin disease that affects approximately 2% of the US population. The cutaneous lesions characteristic of psoriasis can cause physical, psychological, and social dysfunctions in affected individuals.1 The pathophysiology of psoriasis consists of an abnormal immune response. T cells in the dermis and epidermis are overactivated, which triggers the release of proinflammatory cytokines and hyperproliferation of keratinocytes. This, in turn, manifests as the skin lesions that are the hallmark of psoriasis.
Hand and Foot Psoriasis
For hand and foot psoriasis, lesions may occur on:
- the palms of the hands
- the soles of the feet
- the dorsal surface of the hands and feet.
In addition to exhibiting plaque-type lesions, this variant of psoriasis can also include fissuring, crusting, erythema, and recurrent painful pustules. Hand and foot psoriasis occurs in approximately one-third of the psoriatic population, and interestingly, many patients with this disease do not have psoriasis on other parts of their body. The biological basis for the differences in affected body area is not known.2,3
Hand and foot psoriasis may make routine tasks, such as writing, hand shaking, and walking very difficult for affected individuals. Not only can this profoundly affect their quality of life, it can also greatly affect their family members and caregivers. To better understand these impacts, investigators conducted a survey of patients with and without hand and foot involvement to compare disease severity.2 The results indicated that patients with hand and foot psoriasis reported significantly greater functional disability and physical discomfort, such as burning and soreness, as compared with those who did not have hand and foot involvement.
Interestingly, the survey revealed that the added disabilities were related to physical activities in general and not to social issues, which dispels the assumption that psoriasis on the hands and feet can lead to greater psychosocial dysfunction than psoriasis on other parts of the body. Furthermore, the survey found that for patients who experienced associated pain and discomfort from hand and foot psoriasis, complete clearing of the lesions was not as important to them as pain reduction.
Limitations of Conventional Treatment
Hand and foot psoriasis is often refractory to treatment, and the lack of effective therapeutic options creates an unmet medical need. (See Table 1 for a summary of treatment modalities.) Topical therapies elicit insufficient response rates, in part because it is more
difficult for drugs to penetrate the thicker skin of the palms and soles, as compared with skin absorption on other regions of the body. The biological basis for the difficulty in treating with conventional systemic agents remains unclear. At present, a combination of topical psoralen photochemotherapy and systemic retinoids is frequently used. Other treatment options include cyclosporine and methotrexate; each has proven to be beneficial for some patients. However, several of these systemic treatments must be administered at high doses in order to be effective for the hands and feet. This can lead to significant side-effects, such as a higher risk of skin cancer, infections, teratogenicity, and hyperlipidemia.4-6
Efalizumab is a recombinant, humanized anti-CD11a monoclonal IgG1 antibody that has been approved for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients.7 The biological basis for the therapeutic benefits of efalizumab is its inhibition of T-cell-mediated immune responses. Efalizumab targets the T-cell adhesion molecule, leukocyte functionassociated antigen 1 (LFA-1), which is present on the surface of T cells and is made up of a heterodimer of CD11a and CD18 proteins. Interaction between LFA-1 and intracellular adhesion molecule 1 (ICAM-1), a cell surface protein of the antigen-presenting cell (APC), serves as the predominant adhesion interface between T cells and their APCs. LFA-1/ICAM-1 interaction is critical for T-cell activation and trafficking. By binding to the CD11a subunit of LFA-1 with high affinity and specificity, efalizumab prevents CD11a interaction with ICAM-1, thereby inhibiting the initiation of an immune response and the release of inflammatory cytokines involved in keratinocyte proliferation and the development of psoriatic lesions.21
Efalizumab for the Treatment of Moderate-to-Severe
The safety and efficacy of efalizumab for the treatment of moderate-to-severe plaque psoriasis have been well documented in multiple, phase III, randomized, placebocontrolled, multicenter studies.22-25 In these studies, 27%-33% of efalizumab-treated patients achieved 75% improvement on the Psoriasis Area and Severity Index (PASI-75) after 12 weeks of treatment. Furthermore, after 24 weeks of continuous efalizumab treatment, 44% of treated patients achieved PASI-75.24,26 Leonardi, et al. found that response can be maintained with long-term treatment, i.e., 45% of patients achieved PASI-75 after 144 weeks of continuous efalizumab treatment.27
Efalizumab for the Treatment of Hand and Foot
A recently published case report series suggested benefits for efalizumab in the treatment of patients with hand and foot psoriasis.4 The report presents cases of 17 patients: four men and 13 women with plaque-type (n=11) or pustular-type (n=5) hand and foot psoriasis, and one patient with both plaque- and pustular-type. The age range of the patients was 29-33 years and the range of their disease duration was 3-30 years. Hand and foot psoriasis in these patients was refractory to various treatments, including topicals, methotrexate, cyclosporine, prednisone, acitretin, psoralen UVA phototherapy, and the tumor necrosis factor inhibitor etanercept. Each of these patients received subcutaneous injections of efalizumab (1mg/kg/wk), and the treatment outcome was measured by PASI, the Physician’s Global Assessment (PGA), or the affected body surface area. With efalizumab treatment, the patients achieved 50%-100% clearance of their hand and foot psoriasis as early as 2 weeks following the start of treatment. For two of the patients, it took approximately 1 year to achieve 85% and 100% clearance of their disease. One patient had additional psoriasis in the fingernails and toenails with pitting and onycholysis, which also cleared with efalizumab treatment. Efalizumab was generally well tolerated by all of the patients in this case series, with one occurrence each of hemolytic anemia and mild myalgia; three patients developed mild flu-like symptoms, which were determined to be reversible drug-related adverse events.
A 12-week, phase IV, randomized, double-blind, placebo-controlled study was recently completed to assess the efficacy and safety of efalizumab in 75 enrolled patients with chronic moderate-to-severe hand and foot psoriasis. The study population included patients with or without pustules, and with or without psoriasis at locations other than the hands and feet, who had a PGA rating of moderate (3) or severe (4) for hand and/or foot psoriasis and no previous exposure to the study drug. Patients were administered efalizumab 1mg/kg/wk (n=52) or placebo (n=28). In a preliminary report of the data collected, 46.2% of efalizumab-treated patients achieved a PGA rating of clear (0), almost clear (1) or mild (2) after 12 weeks of treatment versus 17.9% of placebo-treated patients.12,28 The incidence of adverse events in patients treated with efalizumab was similar to those treated with placebo, which was consistent with the safety profile observed in previous phase III studies.
Physicians and caregivers may sometimes underestimate the impact of hand and foot psoriasis on affected individuals; simple routine and important functions can become physically and psychosocially challenging for these patients. Efforts to find effective long-term therapeutic options with favorable safety profiles remain an elusive achievement. As a prerequisite to fulfilling this unmet medical need, basic research must be conducted to gain a thorough understanding of the pathophysiology of hand and foot psoriasis and to further determine whether there are distinct disease pathways that lead to the plaque versus pustular forms of this disease. To date, the options available for treatment have been limited by inadequate response to therapy and/or toxicity related to increased dosage and long-term use. As noted above, recently published case studies and preliminary results from a phase IV study have shown potential benefits of efalizumab in the treatment of hand and foot psoriasis. It would be of great interest to evaluate the effects of efalizumab in the long-term treatment of hand and foot psoriasis.
- Fortune DG, Main CJ, O’Sullivan TM, et al. Quality of life in patients with psoriasis: the contribution of clinical variables and psoriasis-specific stress. Br J Dermatol 137(5):755-60 (1997 Nov).
- Pettey AA, Balkrishnan R, Rapp SR, et al. Patients with palmoplantar psoriasis have more physical disability and discomfort than patients with other forms of psoriasis: implications for clinical practice. J Am Acad Dermatol 49(2):271-5 (2003 Aug).
- Enfors W, Molin L. Pustulosis palmaris et plantaris. A follow-up study of a ten-year material. Acta Derm Venereol 51(4):289-94 (1971).
- Fretzin S, Crowley J, Jones L, et al. Successful treatment of hand and foot psoriasis with efalizumab therapy. J Drugs Dermatol 5(9):838-46 (2006 Oct).
- Marsland AM, Griffiths CE. Treatments for chronic palmoplantar pustular psoriasis. Skin Therapy Lett 6(12):3-5 (2001 Nov).
- Marsland AM, Chalmers RJ, Hollis S, et al. Interventions for chronic palmoplantar pustulosis. Cochrane Database Syst Rev (1):CD001433 (2006).
- Raptiva® [efalizumab] (package insert). South San Francisco, Calif: Genentech, Inc. (2005 Jun).
- Lassus A, Geiger JM. Acitretin and etretinate in the treatment of palmoplantar pustulosis: a double-blind comparative trial. Br J Dermatol 119(6):755-9 (1988 Dec).
- Myers W, Christiansen L, Gottlieb AB. Treatment of palmoplantar psoriasis with intramuscular alefacept. J Am Acad Dermatol 53(2 Suppl 1):S127-9 (2005 Aug).
- Prossick TA, Belsito DV. Alefacept in the treatment of recalcitrant palmoplantar and erythrodermic psoriasis. Cutis 78(3):178-80 (2006 Sep).
- Erkko P, Granlund H, Remitz A, et al. Doubleblind placebo-controlled study of long-term lowdose cyclosporin in the treatment of palmoplantar pustulosis. Br J Dermatol 139(6):997-1004 (1998 Dec).
- Leonardi CL, Sobell JM, Sofen H, et al. Phase IV study to evaluate the safety and efficacy of efalizumab for treatment of hand and foot psoriasis. J Am Acad Dermatol 56(2):AB48 (2007 Feb).
- Weinberg JM. Successful treatment of recalcitrant palmoplantar psoriasis with etanercept. Cutis 72(5):396-8 (2003 Nov).
- Mihara M, Hagari Y, Morimura T, et al. Itraconazole as a new treatment for pustulosis palmaris et plantaris. Arch Dermatol 134(5):639-40 (1998 May).
- Bhushan M, Burden AD, McElhone K, et al. Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo controlled study. Br J Dermatol 145(4):546-53 (2001 Oct).
- Duweb GA, Abuzariba O, Rahim M, et al. Occlusive versus nonocclusive calcipotriol ointment treatment for palmoplantar psoriasis. Int J Tissue React 23(2):59-62 (2001).
- Kragballe K, Larsen FG. A hydrocolloid occlusive dressing plus triamcinolone acetonide cream is superior to clobetasol cream in palmo-plantar pustulosis. Acta Derm Venereol 71(6):540-2 (1991).
- Kumar B, Sandhu K, Kaur I. Topical 0.25% methotrexate gel in a hydrogel base for palmoplantar psoriasis. J Dermatol 31(10):798-801 (2004 Oct).
- Kumar B, Kumar R, Kaur I. Coal tar therapy in palmoplantar psoriasis: old wine in an old bottle? Int J Dermatol 36(4):309-12 (1997 Apr).
- De Rie MA, Van Eendenburg JP, Versnick AC, et al. A new psoralen-containing gel for topical PUVA therapy: development and treatment results in patients with palmoplantar and plaquetype psoriasis, and hyperkeratotic eczema. Br J Dermatol 132(6):964-9 (1995 Jun).
- Werther WA, Gonzalez TN, O’Connor SJ, et al. Humanization of an anti-lymphocyte functionassociated antigen (LFA)-1 monoclonal antibody and re-engineering of the humanized antibody for binding to rhesus LFA-1. J Immunol 157(11):4986-95 (1996 Dec).
- Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 349(21):2004-13 (2003 Nov).
- Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 290(23):3073-80 (2003 Dec).
- Menter A, Gordon K, Carey W, et al. Efficacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis. Arch Dermatol 141(1):31-8 (2005 Jan).
- Leonardi CL, Papp KA, Gordon KB, et al. Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol 52(3 Pt 1):425-33 (2005 Mar).
- Gottlieb AB, Hamilton T, Caro I, et al. Longterm continuous efalizumab therapy in patients with moderate to severe chronic plaque psoriasis: updated results from an ongoing trial. J Am Acad Dermatol 54(4 Suppl 1):S154-63 (2006 Apr).
- Leonardi C, Menter A, Hamilton T, et al. Efalizumab: results of a 3 year continuous dosing study for the long-term control of psoriasis. Br J Dermatol, submitted June 2007.
- Genentech. Genentech announces positive results from a phase IV study of Raptiva in patients with moderate-to-severe hand and foot psoriasis [press release]. February 2, 2007. http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=10447, last accessed August 13, 2007.