Psoriatic arthritis: Pathogenesis and novel immunomodulatory approaches to treatment

1476-8518-3-6 1476-8518 Review Psoriatic arthritis: Pathogenesis and novel immunomodulatory approaches to treatment Cassell Sarah scassell@ucsd.edu Kavanaugh Arthur akavanaugh@ucsd.edu

Center for Innovative Therapy, Division of Rheumatology, Allergy, and Immunology, The University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0943, USA

Journal of Immune Based Therapies and Vaccines 1476-8518 2005 3 1 6 http://www.jibtherapies.com/content/3/1/6 16138929 10.1186/1476-8518-3-6 05 7 2005 02 9 2005 02 9 2005 2005 Cassell and Kavanaugh; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis and psoriasis. PsA runs a variable course, from mild synovitis to severe, progressive, erosive arthropathy. The pathogenesis of PsA involves alteration in the components of the immune response, although the exact cause of PsA is unknown. A number of patients with severe peripheral arthritis fail to respond to standard conventional therapy. Advances in biotechnology and in our understanding of the immunopathogenesis of PsA have led to great interest and progress in regards to biologic treatments for PsA. Notable success achieved with recently introduced biologic therapies has paved the way for further research and develpoment of additional therapies that should improve outcomes for affected patients.

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis and psoriasis. Joint involvement is heterogeneous, and may consist of spondyloarthropathy, as well as oligoarticular and polyarticular peripheral arthritis. PsA runs a variable course, from mild synovitis to severe, progressive, erosive arthropathy. PsA is classified as one of the subtypes of spondyloarthropathy, sharing clinical features such as asymmetric joint involvement, an oligoarticular arthritis pattern, a similar frequency in men and women, the common occurrence of enthesitis and dactylitis, infrequent rheumatoid factor and anti-cyclic-citrullinated-peptide seropositivity, and extra-articular manifestations such as iritis.

Epidemiology

Psoriasis occurs in about 2% of the population 1. PsA has been reported in 7% to 42% of patients with psoriasis 2. The prevalence of PsA in the US has been estimated as 0.67% 3. However, estimates of prevalence are variable, due in part to the heterogeneity of the disease as well as a lack of validated diagnostic criteria 4.

In general, skin involvement precedes joint disease, often by years. However, PsA precedes skin psoriasis in about 15% of patients, and the two occur simultaneously in about 20%. Some reports suggest that PsA is more common in patients with severe psoriasis 56. A recent study suggested a correlation between the extent of skin and joint severity only among patients with simultaneous onset of skin and joint manifestations 7.

Pathogenesis

The exact cause of PsA is unknown, although genetic, environmental, and immunologic factors clearly play important roles. The pathogenic connection between psoriasis and arthritis is not clear, although both are immunologically mediated.

Genetic factors

Most studies document a familial predisposition to both psoriasis and PsA. More than 40% of patients with PsA have first degree family members with either skin or joint disease 89. Several genetic susceptibility loci have been proposed, with the strongest effect residing within the major histocompatibility complex (MHC). Population studies in PsA have shown increased frequency of HLA-B13, B17, B27, B38, B39, DR4 and DR7 81011. In a comparison of 158 patients with PsA to 101 patients with uncomplicated psoriasis, HLA-B7 and B27 were more common among patients with PsA, whereas B17, Cw6 and DR7 were more common among patients with uncomplicated psoriasis 8. Some of these associations may be confounded by linkage disequilibrium. HLA-B27 has been associated with spinal disease in which radiological sacroiliitis is present. A symmetric pattern of peripheral PsA appears related to HLA-DR4 812. The strongest susceptibility locus for psoriasis is on chromosome 6p, termed PSORS1 113141516. Other psoriasis susceptibility loci are located on chromosomes 17q25 (PSORS2), 4q34 (PSORS3), 1q (PSORS4), 3q21 (PSORS5), 19p13 (PSORS6), 1p (PSORS7), and 17q25 (RUNX1) 1.

Other genes within the MHC region and non-HLA associations have been explored. A TNF-α promoter polymorphism or a gene in linkage disequilibrium with TNF-α may predispose or increase susceptibility to psoriasis and PsA 17. One study looking at the TNFβ+252 and TNFα-308 polymorphisms did not find the alleles more frequently in PsA patients than matched controls, but did find both alleles were significantly associated with the presence of joint erosions and the progression of joint erosions in early PsA 18. A meta-analysis showed the TNFα-238 variant in Caucasian PsA patients was a significant risk factor for PsA 19. A recent study pointed to Cw6 and MHC class I chain-related A (MICA)-A9 as being the strongest genetic susceptibility factors for PsA 20.

Environmental factors – infection, trauma

Both viral and bacterial infections have been implicated as causative agents in PsA. Support for the role of bacterial antigens in the pathogenesis of psoriasis and PsA comes from indirect observation of enhanced humoral and cellular immunity to gram-positive bacteria typically found in the psoriatic plaques 21. However, psoriatic plaques often get secondarily infected, thus the cause-effect relationship of bacteria and psoriasis is difficult to prove. One study of sera from patients with PsA showed higher levels of antibody to streptococcal exotoxin, which provides some evidence of a link between streptococcal infection and articular inflammation 22. The possibility that PsA might be virally induced has been proposed, although never confirmed 2324. Physical trauma may result in the onset of psoriasis (Koebner Phenomenon) and, theoretically, PsA at the sites of injury. This association would highlight potential association between innate and specific immunity. There are a number of case reports suggesting a possible role for trauma in PsA, but this has not been evaluated in a prospective manner.

Immunologic factors

Both psoriasis and PsA are immunologically mediated. Characteristic pathologic features of PsA are synovial lining layer cell hyperplasia, inflammatory cell accumulation and prominent vascularity. T lymphocytes, particularly CD8+ cells, may play important pathogenic roles. Activated T cells have been noted in affected tissue, both skin and joint 2526. A predominance of CD8+ T lymphocytes with clonal expansion have been found in PsA synovial fluid leading to the proposal that CD8+ T cells drive the immune response 27. This is further supported by the fact that CD8+ T cells also dominate the infiltrate at marrow sites adjacent to entheseal inflammation, an early area of involvement 28. An analysis of T cell receptor beta chain variable (TCRβV) gene repertoires revealed common expansions in both skin and synovial inflammatory sites, suggesting an important role for cognate T cell responses in the pathogenesis of PsA and that the inciting antigen may be identical or homologous between afflicted skin and synovium 29.

The cytokine network in the psoriatic skin and synovium is dominated by monocyte and T-cell derived cytokines: IL-1β, IL-2, IL-10, IFN-γ and TNF-α 30. In PsA synovium, higher levels of IFN-γ, IL-2 and IL-10 have been detected than in psoriatic skin. One study of cytokine staining in PsA synovium showed IL-1α, IL-1β, IL-8, IL-15, IFN-γ and TNF-α staining localized to the lining layer and perivascular macrophages 31. These cytokines can induce proliferation and activation of synovial and epidermal fibroblasts, leading to fibrosis in patients with longstanding PsA. TNF-α, a key proinflammatory cytokine, induces the production of other inflammatory cytokines such as IL-1, IL-6, and granulocyte-macrophage colony-stimulating factor, chemokines such as IL-6, degradative enzymes such as several matrix metalloproteinases (MMPs) and other factors. TNF-α mediates a number of biological processes that can result in joint damage including stimulation of bone resorption, inhibition of bone formation, and inhibition of synthesis of proteoglycans 3233. Angiogenic factors such as TNF-α and vascular endothelial growth factor (VEGF) may contribute to vascular proliferation 3435.

While the mechanisms governing psoriatic skin and joint involvement are similar, there are distinctions. For example, cutaneous lymphocyte associated (CLA) antigen, an adhesion molecule that identifies lymphocytes that preferentially traffic to the skin, is upregulated on lymphocytes in psoriatic skin but is minimally expressed on cells in the PsA synovium 36.

Clinical Features

Wright and Moll recognized several patterns of PsA: isolated distal interphalangeal disease, peripheral oligoarthritis, peripheral polyarthritis, and spondyloarthropathy. These clinical phenotypes are not fixed but are interchangeable, and individual patients can switch phenotypes 37. The most important distinction as regards outcome appears to be oligo- versus poly-articular joint involvement.

Extra-articular manifestations of PsA are important aspects of the disease, the most common is the psoriatic skin lesion, which may affect all areas of the skin. Dactylitis is typical in PsA and presents as inflammation of the whole digit, joints and tendon sheaths. Enthesitis, inflammation at the site of tendon, ligament or synovial membrane insertion into bone, is characteristic of PsA and may represent the earliest site of involvement. Other extra-articular manifestations include the presence of iritis, mouth ulcers, and urethritis.

PsA has several characteristic radiographic features which include lack of periarticular osteopenia, destruction of interphalangeal joints with widening of the joint spaces, pencil-in-cup changes in the hands and feet, ankylosis, periosteal reaction, and spur formation 38.

The course of PsA is variable. Patients who have five or more involved joints at presentation are more likely to have progressive disease. Some patients have few episodes and completely recover, but recent studies demonstrated that many patients have persistent and severe courses 394041. Damage in PsA occurs early and progresses over time, with increasing deformities and limitation of daily activity 42. Patients with PsA have increased mortality compared to the general population. More severe disease, as manifested by higher ESR and radiologic scores at presentation, is a predictive factor of mortality 43.

Treatment of PsA

Conventional treatment

Mild joint symptoms may respond to non-steroidal anti-inflammatory drugs (NSAIDs) 42. Systemic steroids can be used, but may cause side effects and rebound worsening of psoriasis 44. Patients who are unresponsive to NSAID therapy or who have progressive disease may require disease modifying anti-rheumatic drugs (DMARDs) (eg methotrexate [MTX], leflunomide, sulfasalazine [SSZ], cyclosporine [CsA]).

MTX is considered by many rheumatologists the DMARD of choice because of its remarkable efficacy in ameliorating both skin and joint disease, its rapid onset, and its acceptable safety profile 4546. However, 16–30% of patients treated with MTX discontinue it because of toxicity 4748. Leflunomide, an antipyrimidine drug that interferes with T-cell activation, has been shown to be effective in improving both joint and skin symptoms 49. The most common side effects seen with leflunomide are diarrhea and increased transaminases. SSZ has been shown to be helpful for peripheral arthritis but not for axial disease 50. CSA improves both joint inflammation and skin lesions in PsA, but is not frequently used because of its toxicities, the most worrisome being hypertension and nephrotoxicity 4851. Likewise, gold compounds and other drugs have been reported to ameliorate arthritis in some PsA patients, but are rarely used secondary to side effects and toxicities.

Biologic Agents

In recent years, greater understanding of immunopathology and advances in biotechnology facilitating the ability to design and produce novel biologic agents have led to exciting breakthroughs in the treatment of autoimmune disease, including psoriasis and PsA 52. The development of novel biologic agents has been further encouraged by the unmet need for better treatments and the positive results with their use in other autoimmune diseases, particularly rheumatoid arthritis (RA). The most significant experience of the use of biologics in treatment of PsA is with TNF-α inhibitors.

Tumor necrosis factor-alpha (TNF-α) inhibitors

Given its pro-inflammatory potential and its elevated levels in RA and PsA, TNF-α was identified as an attractive target for biologic therapies. TNF-α inhibitors have been used with great success to suppress joint inflammation in RA, inducing not only marked improvement in the signs and symptoms of disease, but also substantially improved functional status and quality of life 535455. Additionally, they have been shown to attenuate the progression of radiographic joint damage. Adverse effects have been reported, but in general these agents are well-tolerated. These encouraging results spurred interest in using TNF-α inhibitors in PsA. Currently there are three TNF-α inhibitors available: 1) etanercept, a fusion protein consisting of a dimer of the extracellular portion of the type II TNF receptor (p75) linked to the Fc portion of IgG1, 2) infliximab, a chimeric monoclonal antibody specific for TNF-α, and 3) adalumimab, a human monoclonal antibody specific for TNF-α.

1. Etanercept

Etanercept has been proven effective for the treatment of PsA 5657. The first double-blind, placebo controlled clinical trial of etanercept in PsA was in 60 patients with long-standing disease. The etanercept group showed significant improvement in all measures of disease activity compared with the placebo group at 12 weeks. The primary endpoint for arthritis activity, the Psoriatic Arthritis Response Criteria (PsARC), a composite index, was achieved by 87% versus 23% of the etanercept and placebo groups respectively 58. A secondary endpoint was the American College of Rheumatology composite response criteria (ACR), a score based on 20%, 50%, or 70% improvement 59. ACR20 responses were 73% and 13% in the etanercept and placebo groups respectively 56. For psoriasis, the primary endpoint was 75% improvement in the Psoriasis Area and Severity (PASI) score (PASI75). Of patients with >3% body surface involvement, 26% of etanercept treated patients achieved PASI75 versus none in the placebo treated group 56. Disability, as assessed by responses on the health assessment questionnaire (HAQ), significantly improved in the etanercept group. An open-label extension of this study revealed sustained efficacy in joints, further improvement of skin disease, ability to decrease or discontinue concomitant methotrexate and prednisone, and continued tolerability 60.

Another phase III clinical trial of etanercept in 205 patients with PsA confirmed and extended earlier findings. ACR20 response rates were achieved by 59% of the etanercept group and 15% of the placebo group at 12 weeks (P < 0.001). This clinical response was sustained for 24 weeks. Of those meeting criteria for PASI evaluation, the etanercept group showed on average 47% improvement compared to no improvement in the placebo group (P < 0.001) 57.

Etanercept has been observed to slow and halt radiographic structural damage in PsA. A one year study of 205 patients revealed that at twelve months the radiographic disease progression in the etanercept group was inhibited (Sharp score: -.03 units) compared with worsening in the placebo group (Sharp score: +1.00 units) (p = .0001) 61.

2. Infliximab

Open-label studies of infliximab in PsA showed significant decreases in the signs and symptoms of joint inflammation and skin disease 626364. This led to double blind, placebo controlled trials, which also revealed positive results 6566. The infliximab multinational psoriatic arthritis controlled trial (IMPACT) enrolled 104 patients in a double blind, randomized, placebo-controlled trial for 16 weeks, followed by blinded single-crossover design through 50 weeks 65. ACR20/50/70 responses at week 16 were 69%/49%/29% in the active treatment group compared to 8%/0%/0% in the placebo group. These results were sustained at 50 weeks with ACR 20/50/70 responses in the infliximab group of 72%/54%/35%. Of the placebo-treated patients who crossed over to active treatment at week 16, ACR20/50/70 responses increased to 77%/49%/30%. This study also assessed dactylitis and enthesitis, two important characteristics of PsA that had not previously been included in clinical trials. Significant improvements were seen in dactylitis and enthesitis with infliximab therapy. Of particular note in this study was the dramatic improvement in skin psoriasis seen with infliximab treatment. Thus, PASI75 was achieved by 12 of 14 infliximab patients whereas there was overall worsening of skin scores in the placebo treated group. This effect was sustained at week 50. Also, 8 of 16 placebo patients who switched to infliximab treatment after week 16 achieved PASI75 at week 50.

These results were confirmed with the subsequent larger phase 3 IMPACT 2 study 67. In this trial, 200 patients with active PsA were randomized to receive infliximab or placebo for 24 weeks. ACR 20/50/70 scores at week 24 in the infliximab group were 54%/41%/27% and 11%/4%/2% in the placebo group. Again, skin improvement was very impressive, with 60% of the infliximab group achieving PASI75 at week 24, whereas only 1% of the placebo group did. Statistically significant improvements in measures of functional status and quality of life (measured by HAQ and SF-36, respectively) were seen, as were improvements in dactylitis and enthesopathy.

Two studies have shown that infliximab can inhibit radiographic disease progression. In a double-blind, placebo controlled trial of 200 PsA patients (IMPACT2), patients treated with infliximab had significantly less radiographic disease progression at week 24, as measured by the van der Heijde-Sharp method modified for PsA (-0.7 +/- 2.53 versus .82 +/- 2.62, for infliximab versus placebo treated patients respectively; p < 0.001) 68. An analysis of patients from the IMPACT1 study showed that at 50 weeks, radiographic progression of disease was inhibited in both the group treated with infliximab throughout the trial as well as in the group receiving infliximab from week 16 through week 50 69.

3. Adalumimab

Adalumimab was assessed in PsA in a phase III, placebo-controlled, double blind study, the Adalimumab Effectiveness in PsA Trial (ADEPT) 70. 151 patient received adalumimab and 162 received placebo. Adalumimab treated patients showed rapid improvements. At week 24 ACR20, 50, and 70 scores for adalumimab were 57%, 39%, and 23% respectively versus 15%, 6%, and 1% for placebo. PASI50, 75 and 90 scores for adalumimab and placebo respectively were 75%, 59%, and 42% versus 12%, 1%, and 0% 70.

Adalimumab was also shown to inhibit radiographic disease progression. In the ADEPT trial, at week 24 mean change in modified total Sharp Scores (mTSS) was -0.2 in infliximab treated patients compared with +1.0 in placebo treated patients (p <= .001). All patients were allowed to go into an open label extension after week 24. Patients who started in the placebo arm and crossed to the adalimumab open label arm at week 24 had mTSS scores of +1.0 and +1.0 at weeks 24 and 48 respectively, showing no further radiographic progression after they started adalimumab. The patients originally in the adalimumab arm who extended into open label treatment had mTSS scores of -0.2 and 0.1 at weeks 24 and 48 respectively. Assessments at week 48 showed that adalimumab maintained the lack of radiographic change 71.

With all TNF-α inhibitors there have been concerns about safety issues, particularly infections, serious infections and opportunistic infections such as reactivation of latent tuberculosis. Appropriate monitoring for signs and symptoms of infection is required before and during treatment. While other adverse events have been reported at relatively low rates, careful monitoring of patients on these new biologic agents is quite important.

Alefacept

Another biologic agent in development for PsA is alefacept, which was approved in the US for the treatment of psoriasis in 2003. Alefacept is a human LFA-3/IgG1 fusion protein and is under clinical investigation for the treatment of PsA and RA. The LFA-3 portion of alefacept binds to CD2 receptors on T cells to block the natural interaction between LFA-3 on antigen-presenting cells and CD2 on T cells. Blockade of the LFA-3/CD2 interaction, a key co-stimulatory pathway, can inhibit T-cell activation. The IgG1 portion of alefacept can bind to FcγRIII (CD16) IgG receptors on accessory cells (e.g. natural killer cells) and may induce granzyme-mediated apoptosis 5272.

Alefacept was evaluated as a treatment for psoriasis in multicenter, randomized, placebo-controlled, double blind study. Two hundred twenty-nine patients with chronic psoriasis received intravenous injection of alefacept at different dosages. The mean reduction in the PASI score 12 weeks after treatment was greater in the alefacept groups than the placebo group 73.

A small study suggested that alefacept may also improve both skin and joint symptoms in PsA 74. In a single center open-label study, 11 patients with PsA received intravenous 7.5 mg alefacept once weekly for 12 weeks. Synovial tissue biopsies of an index joint were obtained by arthroscopy at baseline and at weeks 4 and 12. Clinically, some degree of improvement in arthritis was observed in six patients (55%) at the completion of the treatment. A similar proportion of patients achieved 50% amelioration of skin disease. This study supports the notion that T cell activation plays an important role in chronic inflammatory diseases and effective blockade of the LFA-3/CD2 interaction may be useful for treating PsA.

Additionally, a double blind, placebo controlled trial assessed the combination of alefacept and methotrexate in 185 PsA patients. An ACR20 response was achieved by 54% of the alefacept group versus 24% of the placebo group. 53% of the alefacept group achieved PASI50 compared with 17% of the placebo group 75. Adverse events in this trial occurring at >5% included: back pain, nasopharyngitis, nausea, URI and increased ALT. There were no serious infections and the serious adverse event rate was 2% 76.

Efalizumab

Leukocyte function associate antigen-1 (LFA-1) is an adhesion molecule expressed on T lymphocytes. It interacts with its ligand, intercellular adhesion molecule (ICAM-1), in ways that may be relevant to the pathogenesis of psoriasis including: stabilizing the binding of antigen-presenting cells to T lymphocytes, facilitating migration of T lymphocytes from circulation into skin, and activation of T lymphocytes 77. Efalizumab is a humanized monoclonal IgG antibody that binds to the alpha-subunit (CD11) of LFA-1 and prevents LFA-1 binding to ICAM-1. In two recent phase 3, randomized, double-bind, placebo-controlled trials, efaluzimab showed efficacy in treating moderate to severe plaque psoriasis, and was recently approved for this use by the US FDA.

Leonardi et al, reported a study of 498 psoriasis patients that showed PASI75 scores at 12 weeks in the treatment groups were achieved in 32.6% of patients versus 2.4% of placebo-treated patients 77. The most common adverse events (headache, fever, chills, nausea, and myalgias) were more frequent in the efalizumab-treated group only during the first two injections, and then decreased to rates similar to placebo. A second study randomized 556 psoriasis patients for twelve weeks with continuation in an open label study 78. At 12 weeks, PASI50/75 were 58.5%/26.6% respectively in efaluzimab-treated patients compared with 13.9%/4.3% in placebo treated patients. These numbers increased at week 24. Patient reported outcomes (dermatology life quality index and itching scale) also improved. Interestingly, during the second twelve weeks there was an increased incidence of arthritis (5.6%); 12 of these 19 cases had had a prior history of arthritis.

Preliminary results from a phase II study of efalizumab in 117 PsA patients showed that treatment did not reach statistical significance as far as achieving an ACR20 reponse at twelve weeks 79.

Other types of biologic agents and future directions

The introduction of TNF-α inhibitors and their tremendous clinical impact has generated considerable interest in exploring other avenues for the treatment of PsA. In addition, it is worth noting that despite the tremendous success achieved in PsA patients treated with TNF-α inhibitors, approximately one-third of patients with moderate to severe PsA have negligible or insufficient responses to such treatment. This has provided the impetus for the development of biologic agents targeting other aspects of the dysregulated immune system. Several promising biologic agents, directed at targets other than TNF-α, are currently under study (Table 1).

Table 1

Biologic agents under consideration for the treatment of Psoriatic arthritis

Suppression of inflammatory mediators

target

agent

comment

IL-1

Anakinra

IL-1 receptor antagonist

IL-8

ABXIL-8

human anti-IL-8 mAb

Modulation of the function of Anti-inflammatory mediators

target

agent

comment

IL-10

rIL-10

recombinant human Th2 cytokine

IL-11

rIL-11

recombinant human Th2 cytokine

Alteration of T cell number and function interaction

target

agent

comment

IL-12

anti-IL-12 mAb

several in development

CD25 (IL-2 receptor)

Daclizumab

humanized anti-CD25 mAb

CD2

Alefacept

human LFA-3/IgG fusion protein

CD11a (LFA-1)

Efalizumab

humanized anti-CD11a mAb

TCR/CD3

huOKT3γ1(ala-ala)

humanized anti-CD3 mAb

CD80/CD86

IDEC-114

humanized anti-CD80 mAb

CTLA4Ig

fusion protein of CTLA-4/Ig

CD40/CD40L

IDEC-131

humanized anti-CD154 mAb

mAb, monoclonal antibody; rIL, recombinant interleukin; IL-2R, LFA, leukocyte function associated antigen; TCR, T-cell receptor; CTLA4Ig, cytotoxic T-lymphocyte-associated antigen 4/immunoglobulin

One approach is the targeting of other inflammatory mediators. ABXIL-8 (Abgenix Inc, Fremont, CA), a human anti-IL-8 monoclonal antibody, binds free IL-8 and may deactivate it in the skin. Effects of IL-8 include T cell and neutrophil activation and chemotaxis, as well as keratinocyte proliferation. IL-8 may also play a role in the vascular responses found in psoriasis 80. A phase II trial in psoriasis showed some improvement in patients' PASI as well as in histological responses 81. IL-1, many of the activities of which overlap with TNF, has been suggested to be of potential importance in the pathogenesis of joint and other inflammation 82. Anakinra (IL-1ra) a homologue of the naturally occurring IL-1 receptor antagonist, has been approved for use in moderate to severely active RA. Other IL-1 inhibiting agents are in development. To date there have not been controlled clinical trials of IL-1 inhibitors in PsA.

Another approach that would suppress inflammation involves the therapeutic use of anti-inflammatory cytokines. For example, among its various activities, Il-10 inhibits INF-γ and promotes TH2 biased cytokine secretion. IL-10 is relatively deficient in psoriatic skin, although it is found in high levels in synovium and serum of PsA patients 83. Recombinant IL-10 (rIL-10) was used in a phase II trial in 14 patients with chronic plaque psoriasis; 71% had more than a 50% reduction of PASI scores 84. It has also been studied in PsA which showed modest improvements in skin but not articular disease 85. Recombinant human IL-11 (rhIL-11) has been shown to have anti-inflammatory activity in vitro and in vivo and has been tested in 12 patients with psoriasis. They showed some improvement in PASI scores 86. However, there are no published reports of it being used in PsA.

Another therapeutic strategy is to target the number or function of immunocompetent cells central to the propagation of the disease. Several therapies have targeted T cells, which have been suggested to play a central role in orchestrating the immune driven inflammation in PsA. Daclizumab, a humanized antibody to the α-subunit of the IL-2 receptor, blocks the binding of IL-2, a vital growth factor for T cells. One trial in 19 psoriatic patients showed IL-2 blockade during the first 4 weeks and variable desaturation after that, which correlated with reversal in disease improvement that had been achieved. Patients with pretreatment PASI score of <36 showed mean reduction in severity by 30% at eight weeks 87. HuOKT3γ1 (ala-ala), a non-FcR-binding monoclonal antibody to CD3 (a component of the T cell receptor complex), modulates the function of T cells without decreasing their numbers. A phase I/II study in seven patients with PsA showed 6/7 achieving ACR70 responses at 30 days and all seven had transient, dose dependent depletion of T cells 88. CD28 is a cell-surface protein on mature T cells and binds to two ligands, CD80 and CD86 on antigen-presenting cells. Blocking this interaction results in incomplete T cell activation. CTLA-4, a natural inhibitor of CD28, binds to CD80/86 molecules with high affinity and competes with CD28. CTLA-4-immunoglobulin (CTLA4Ig) was developed to block the CD 28 and CD80/86 interactions. A phase 1 trial in psoriasis patients showed dose dependent improvement in skin involvement 89. A CTLA-4-Ig construct, abatacept, is in late phase development for the treatment of RA. It will likely be studied in PsA in the near future. IDEC-114, a humanized anti-CD80 monoclonal antibody, has also been developed to block this interaction. A phase I/II trial of IDEC-114 in 35 psoriatic patients showed 40% of patients achieved PASI50 90. Finally, therapies directed at inhibiting IL-12, a cytokine central in driving Th1 biased immune responses, are in the early phases of investigation in psoriasis and PsA.

Conclusion

Appreciation of the unmet clinical need for affected patients, greater understanding of the underlying immunopathophysiology of this common autoimmune disease, and progress in biopharmaceutical development have paved the way for the development of novel biologic agents for PsA. Following closely upon the successes achieved in RA, there have been dramatic clinical efficacy achieved with TNF inhibitors. Substantial improvements have been noted not only as far as the signs and symptoms of arthritis, but also in dactylitis and enthesitis and in skin involvement. Moreover, improvements in functional status and quality of life, and attenuation in the progression of radiographic damage have been achieved. Driven by this success, biologic agents targeting other components of the dysregulated immune response that play major roles in pathogenesis of PsA are actively under study. In the foreseeable future, we can expect further exciting development in immunomodulatory therapies for psoriatic arthritis.

Psoriasis Schon M Boeknck WH NEJM 2005 352 1899 1912 10.1056/NEJMra041320 15872205 Psoriatic arthritis Gladman DD Rheum Dis Clin North Am 1998 24 829 44 10.1016/S0889-857X(05)70044-2 9891713 Estimate of the prevalence of selected arthritis and musculoskeletal diseases in the United States Lawrence RC Hochberg MC Kelsey JL J Rheumatol 1989 16 427 41 2746583 Clinical indicators of progression in psoriatic arthritis: multivariate relative risk mode Gladman DD Farewell VT Nadeau C J Rheumatol 1995 22 675 9 7791162 Psoriatic arthritis in severe psoriasis Little H Harvie JN Lester RS Can Med Assoc J 1975 112 317 9 1109748 Prospective analysis of psoriatic arthritis in patients hospitalized for psoriasis Leonard DG O'Duffy JD Rogers RS Mayo Clin Proc 1978 53 511 8 682678 Psoriatic arthritis: interrelationships between skin and joint manifestations related to onset, course and distribution Elkayam O Ophir J Yaron M Caspi D Clin Rheumatol 2000 19 301 5 10.1007/s100670070005 10941813 HLA antigens in psoriatic arthritis Gladman DD Anhorn KAB Schachter RK Mervart H J Rheumatol 1986 13 586 92 3735281 Psoriatic arthritis – an analysis of 220 patients Gladman DD Shuckett R Russell ML Thorne JC Schachter RK Quart J Med 1987 62 127 41 3659255 Psoriatic arthritis: further epidemiologic and genetic consideration Espinoza LR Psoriatic arthritis Grune & Stratton, Orlando Florida Gerber LH, Espinoza 1985 9 32 HLA class II and T cell receptor gene polymorphisms in psoriatic arthritis and psoriasis Sakkas LI Loqueman N Bird H Vaughan RW Welsh KI Panayi GS J Rheumatol 1990 17 1487 90 2273489 Psoriatic arthritis. Genetics and HLA antigens Eastmon CJ Baillieres Clin Rheumatol 1994 8 263 76 8076387 Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q Tomfohrde J Silverman A Barnes R Science 1994 264 1141 5 8178173 Evidence that a locus for familial psoriasis maps to chromosome 4q Matthews D Fry L Powels A Nat Genet 1996 13 231 3 10.1038/ng1096-231 Genetics of psoriasis: paternal inheritance and a locus on chromosome 6p Burden A Javed S Bailey M J Invest Dermatol 1998 110 958 60 10.1046/j.1523-1747.1998.00213.x 9620305 Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci Veal CD Clough RL Barber RC J Med Genet 2001 38 7 13 10.1136/jmg.38.1.7 11134234 A TNF-α promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis Hohler T Kruger A Schneider PM J Invest Dermatol 1997 109 562 5 10.1111/1523-1747.ep12337469 9326391 Cytokine Gene Polymorphisms: Associations with Psoriatic Arthritis Susceptibility and Severity Balding J Kane D Lingstone W Mynett-Johnson L Bresnihan B Smith O FitzGerald O Arth & Rheum 2003 48 1408 1413 10.1002/art.10935 Meta-Analysis of TNF-Alpha Polymorphisms in Caucasian Psoriatic Arthritis Populations Rahman P Siannis F Butt C Farewell V Peddle L Pellet F Gladman D Ann Rheum Dis 2005 64 SIII 325 MICA rather than MICB, TNFA, or HLA-DRB1 is associated with susceptibility to psoriatic arthritis Gonzalez S Martinez-Borra J Lopez-Vazquez A J Rheumatol 2002 29 973 8 12022360 Etiology and pathogenesis of psoriatic arthritis Vasey FB Psoriatic arthritis Grune & Stratton, Orlando Florida Gerber LH, Espinoza 1985 45 57 Possible involvement of group A streptococci in the pathogenesis of psoriatic arthritis Vasey FB Deitz C Fenske NA J Rheumatol 1982 9 719 22 6757423 Psoriatic arthritis and human immunodeficiency virus infection in Zambia Njobvu P McGill P J Rheumatol 2000 27 1699 702 10914854 Hepatitis C virus infection: prevalence in psoriasis and psoriatic arthritis Taglione EV Martini ML Galluzzo P J Rheumatol 1999 26 370 2 9972971 Immunology of psoriasis and psoriatic arthritis Panayi G Baillieres Clin Rheumatol 1994 8 419 27 8076395 Immunohistochemical markers for arthritis in psoriasis Veale DJ Barnes L Rogers S Fitzgerald O Ann Rheum Dis 1994 53 450 4 7944617 Psoriatic arthritis joint fluids are characterized by CD8 and CD4 T cell clonal expansions that appear antigen driven Costello PJ Winchester RJ Curran SA J Immunol 2001 166 2878 86 11160357 Immunohistological study of enthesis in spondyloarthropathies: comparison in rheumatoid arthritis and osteoarthritis Laloux L Voisin MC Allain J Ann Rheum Dis 2001 60 316 21 10.1136/ard.60.4.316 11247858 Clonal characteristics of T cell infiltrates in skin and synovium of patients with psoriatic arthritis Tassiulas I Duncan SR Centola M Hum Immunol 1999 60 479 91 10.1016/S0198-8859(99)00034-8 10408797 Patterns of cytokine production in psoriatic synovium Ritchlin C Haas-Smith SA Hicks D J Rheumatol 1998 25 1544 52 9712099 Macrophage-derived cytokine and nuclear factor kappa B p65 expression in synovial membrane and skin of patients with psoriatic arthritis Danning CL Illei GG Hitchon C Arthritis Rheum 2000 43 1244 56 10.1002/1529-0131(200006)43:6<1244::AID-ANR7>3.0.CO;2-2 10857783 Tumor necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage Saklatvala J Nature 1986 322 547 9 10.1038/322547a0 3736671 Stimulation of bone resorption and inhibition of bone formation in vitro by human tumor necrosis factors Bertolini DR Nedwin GE Bringman TS Nature 1986 319 516 8 10.1038/319516a0 3511389 Elevated tumor necrosis factor alpha biological activity in psoriatic skin lesions Ettehadi P Greaves MW Wallach D Clin Exp Immunol 1994 96 146 51 8149659 Synovial cytokine and growth factor regulation of MMPs/TIMPs: implications for erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients Fearon U Reece R Smith J Ann N Y Acad Sci 1999 878 619 21 10415789 Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis Pitzalis C Cauli A Pipitone N Arthritis Rheum 1996 39 137 45 8546722 Progression of peripheral joint disease in psoriatic arthritis: a 5-yr prospective study McHugh NJ Balachrishnan C Jones SM Rheumatology 2003 42 778 83 10.1093/rheumatology/keg217 12730539 Psoriatic arthritis Resnick D Niwayama G Diagnosis of bone joint disorders WB Saunder Co, Philadelphia 1981 1103 29 Psoriatic arthritis – an analysis of 220 patients Gladman DD Shuckett R Russell ML Quart J Med 1987 62 127 41 3659255 Psoriatic arthritis: Outcome of disease subsets and relationship of joint disease to nail and skin disease Jones SM Armas JB Cohen MG Br J Rheumatol 1994 33 834 9 8081668 A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience Kane D Stafford L Bresnihan B Fitzgerald O Rheumatology 2003 Oct 1 A multidisciplinary approach to psoriatic arthropathy Pringle F Community Nurse 1999 5 21 2 10513533 Mortality studies in psoriatic arthritis: results from a single outpatient center. II. Prognostic indicators for death Gladman DD Farewell VT Wong K Husted J Arthritis Rheum 1998 41 1103 10 10.1002/1529-0131(199806)41:6<1103::AID-ART18>3.0.CO;2-N 9627021 Psoriasis Christophers E Mrowietz U Fitzpatrick's Dermatology in General Medicine McGraw Hill, New York Freedberg IM, Eisen AZ, Wolff K 5 1999 495 521 Methotrexate therapy in psoriatic arthritis: double-blind study on 21 patients Black RL O'Brian WM Van Scott EJ JAMA 1964 189 141 5 Randomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis Willkens RF Williams HJ Ward JR Arthritis Rheum 1984 27 376 81 6712754 Use of disease-modifying antirheumatic drugs in patients with psoriatic arthritis Marquerie L Flipo RM Grardel B Joint bone spine 2002 69 275 81 10.1016/S1297-319X(02)00396-2 12102274 Life-table analysis of cyclosporin A treatment in psoriatic arthritis: comparison with other disease-modifying antirheumatic drugs Spadaro A Taccari E Mohtadi B Clin Exp Rheumatol 1997 15 609 14 9444416 Efficacy and Safety of Leflunomide in the Treatment of Psoriatic Arthritis and Psoriasis: A Multinational, Double Blind, Randomized, Placebo Controlled Clinical Trial Kaltwasser JP Nash P Gladman D Rosen CF Behrens F Jones P Wollenhaupt J Falk F Mease P for the Treatment of Psoriatic Arthritis Study Group Arthritis Rheum 2004 50 1939 50 10.1002/art.20253 15188371 Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study Clegg DO Reda DJ Mejias E Arthritis Rheum 1996 39 2013 20 8961906 Cyclosporine for plaque-type psoriasis: results of a multidose, double-blind trial Ellis CN Fradin MS Messana JM N Engl J Med 1991 324 277 84 1986287 Role of novel biological therapies in psoriatic arthritis Braun J Sieper J Biodrugs 2003 17 187 99 12749755 The evolving use of TNF inhibitors in rheumatoid arthritis Kavanaugh A Cohen S Cush J J Rheumatol 2004 31 1881 4 15468347 Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis Moreland LW Cohen SB Baumgartner SW J Rheumatol 2001 28 1238 44 11409115 Tumor necrosis factor as a therapeutic target in rheumatoid arthritis and other chronic inflammatory diseases: the clinical experience with infliximab (REMICADE) Bondeson J Maini RN Int J Clin Pract 2001 55 211 16 11351775 Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial Mease P Goffe BS Metz J Lancet 2000 356 385 90 10.1016/S0140-6736(00)02530-7 10972371 Improvement in disease activity in patients with psoriatic arthritis receiving etanercept (Enbrel): results of a phase 3 multicenter clinical trial (abstract) Mease P Kivitz A Burch F Arthritis Rheum 2001 44 suppl 9 S90 Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis Clegg DO Reda DJ Mejias E Arthritis Rheum 1996 39 2013 20 8961906 American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis Felson DT Andersen JJ Boers M Arthritis Rheum 1995 38 727 35 7779114 Enbrel (etanercept) in patients with psoriatic arthritis and psoriasis (poster) Mease PJ Goffe BS Metz J Ann Rheum Dis 2001 60 Suppl 1 146 Etanercept Treatment of Psoriatic Arthritis: Safety, Efficacy, and Effect on Disease Progression Mease PJ Kivitz AJ Burch FX Siegel EL Cohen SB Ory P Salonen D Rubenstein J Sharp JT Tsuji W Arthritis Rheum 2004 50 2264 72 10.1002/art.20335 15248226 Efficacy of infliximab in resistant psoriatic arthritis Salvarani C Cantini F Olivieri I Arthritis Rheum 2003 49 541 5 10.1002/art.11201 12910561 Treatment of psoriatic arthritis with antitumour necrosis factor-alpha antibody clears skin lesions of psoriasis resistant to treatment with methotrexate Ogilvie AL Antoni C Dechant C Br J Dermatol 2001 144 587 9 10.1046/j.1365-2133.2001.04089.x 11260020 Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumor necrosis factor α (infliximab) in spondyloarthropathy: an open pilot study Van den Bosch F Kruithof E Baeten D Ann Rheum Dis 2000 59 428 33 10.1136/ard.59.6.428 10834859 The one-year results of the infliximab multinational psoriatic arthritis controlled trial Antoni C Kavanaugh A Kirkham B Arthritis Rheum 2003 ACR abstract S604 Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondyloarthropathy Van den Bosch F Kruithof E Baeten D Arthritis Rheum 2002 46 755 65 10.1002/art.511 11920412 Infliximab Improves Signs and Symptoms of Psoriatic Arthritis: Results of the IMPACT 2 Trial Antoni Krueger De Vlam Birbara Beutler Guzzo Zhou Dooley Kavanaugh Ann Rheum Dis 2005 000 1 8 Infliximab Inhibits Progression of Radiographic Damage in Patients With Active Psoriatic Arthritis: Results for Impact 2 Trial van der Heijde D Kavanaugh A Beutler A Guzzo C Zhou B Dooley L Antoni CE Krueger GG Gladman D Ann Rheum Dis 2005 64 SIII 109 Antoni CE Kavanaugh A Gladman D Wassenberg S Zhou B Beutler A Bermester G Furst DE Weisman M Ebner W Kalden JR Smolen J van der Heijde D Ann Rheum Dis 2005 64 SIII 107 Adalimumab Therapy in Patients with Psoriatic Arthritis: 24-week Results of a Phase III Study Mease P Gladman D Ritchlin C Ruderman E Steinfeld S Choy E Perdok R Weinberg M Arthritis Rheum 2004 50 4097 Adalimumab Treatment Effects on Radiographic Progression of Joint Disease in Patients with Psoriatic Arthritis: Result from ADEPT Mease PJ Sharp JI Ory P Gladman DD Ritchlin CT Choy EH Weinberg EH Ann Rheum Dis 2005 64 SIII 320 An overview of infliximab, etanercept, efalizumab, and alefacept as biologic therapy for psoriasis Weinberg JM Clin Ther 2003 25 2487 505 10.1016/S0149-2918(03)80313-2 14667953 Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes Ellis CN Krueger GG N Engl J Med 2001 345 248 55 10.1056/NEJM200107263450403 11474662 Alefacept treatment in psoriatic arthritis. Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis Kraan MC van Kuijk AWR Dinant HJ Arthritis Rheum 2002 46 2776 84 10.1002/art.10543 12384938 Efficacy of Alefacept in Combination with Methotrexate in the Treatment of Psoriatic Arthritis Mease P Gladman D Keystone E Ann Rheum Dis 2005 64 SIII 324 Safety of Alefacept in Combination with Methotrexate in the Treatment of Psoriatic Arthritis Gladman D Mease P Keystone E Ann Rheum Dis 2005 64 SIII 324 325 Extended efalizumab therapy improves chronic plaque psoriasis: Results from a randomized phase III trial Leonardi Papp Gordon Menter Feldman Cato Walicke Compton Gottlieb J Am Acad Dermatol 2005 52 425 433 10.1016/j.jaad.2004.09.029 15761420 Efficacy and Safety Observed During 24 Weeks of Efalizumab Therapy in Patients with Moderate to Severe Plaque Psoriasis Menter Gordon Carey Hamilton Glazer Caro Li Gulliver Arch Dermatol 2005 141 31 38 10.1001/archderm.141.1.31 15655139 http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=7287 Modulation of keratinocyte-derived interleukin-8 which is chemotactic for neutrophils and T lymphocytes Barker JN Jones ML Mitra RS Am J Pathol 1991 139 869 876 1681733 Patterns of cytokine production in psoriatic synovium Singri P West DP Gordon KB Arch Dermatol 2002 138 657 663 10.1001/archderm.138.5.657 12020229 Interleukin-1 receptor antagonist Bresnihan B Cunnane G Rheum Dis Clin North Am 1998 24 187 199 10.1016/S0889-857X(05)70029-6 Patterns of cytokine production in psoriatic synovium Ritchlin C Haas-Smith SA Hicks D J Rheum 1998 25 1544 1552 9712099 Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, downregulation of epidermal interleukin-8/CXCR2 pathway and normalization of keratinocyte maturation Reich K Garbe C Blaschke V J Invest Dermatol 2001 116 319 329 10.1046/j.1523-1747.2001.01248.x 11180010 IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function in patients with psoriatic arthritis McInnes IB Illei GG Danning CL J Immunol 2001 167 2161 2168 Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions Trepicchio WL Ozawa M Walter IB J Clin Invest 1999 104 1527 1537 409858 10587516 Successful in vivo blockade of CD25 (high-affinity interleukin 2 receptor) on T cells by administration of humanized anti-Tac antibody to patients with psoriasis Krueger JG Walters IB Miyazawa M J Am Acad Dermatol 2000 43 448 458