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Psoriasis affects approximately 2% of the population in the United States. Because psoriasis is an inflammatory disease with both skin and joint manifestations, dermatology healthcare providers are becoming increasingly aware of the substantial incidence of psoriatic arthritis (PsA) in psoriasis. The purpose of this review is to provide dermatology nurse practitioners with the tools needed to accurately diagnose PsA and adequately manage the broad diversity of patients with PsA. We review the epidemiology, etiology, clinical characteristics, physical examination, and differential diagnosis of PsA. The efficacy and safety of various treatment options for patients with PsA are also reviewed and discussed, with a special emphasis on tumor necrosis factor antagonists. Biologic medications offer the potential for greatly improved efficacy compared with nonsteroidal anti-inflammatory drugs and traditional disease-modifying antirheumatic drugs. Patients with PsA may be spared pain, disability, and joint damage and instead enjoy a greater quality of life through early intervention and effective management of psoriatic disease.
Psoriatic arthritis (PsA) is a chronic, heterogeneous, inflammatory arthropathy associated with psoriasis. PsA may show a variable clinical course involving peripheral and axial joints as well as the skin and nails (Ackermann & Kavanaugh, 2008). Historically, PsA has been poorly understood and mistaken as merely a musculoskeletal complication of psoriasis or a more benign relative of rheumatoid arthritis (RA). Severe joint inflammation, joint deformity, irreversible radiological damage (Rahman, Nguyen, Cheung, Schentag, & Gladman, 2001), and increased mortality observed for some PsA patients all challenge the notion that PsA is a benign arthropathy compared with RA (Wong, Gladman, Husted, Long, & Farewell, 1997). In fact, PsA may have a greater impact on patients' quality of life than RA does, as a result, in part, of feelings of depression and embarrassment about visible skin disease that are common among these patients (Husted, Gladman, Farewell, & Cook, 2001). Given the serious implications of PsA, healthcare providers are beginning to initiate a more aggressive approach toward PsA diagnosis and management. However, guidelines for disease detection still need to be defined.
Although early detection and management of the disease are clearly important in preventing structural joint damage, the varied pattern of disease development complicates diagnosis and treatment for healthcare providers. Unpredictable and inconsistent presentation of the signs and symptoms of the disease have been well-documented (Gladman, 2008). For 67% of PsA patients, arthritis symptoms present approximately 9 years after skin symptoms. Therefore, the likely first point of contact with a PsA patient will be the dermatology office (Gladman, 2008). Dermatology nurses and nurse practitioners, therefore, play key roles in the early detection, evaluation, diagnosis, education, and, potentially, even the overall management of PsA. As patient educators and monitors of disease progression, dermatology professionals may be in the best position to identify underlying PsA in psoriasis patients. The purpose of this review was to provide dermatology nurse practitioners with the tools needed to accurately diagnose PsA and adequately provide disease management support for the broad diversity of PsA patients.
The prevalence of PsA in the U.S. population has been estimated at 0.25% (Gelfand et al., 2005), and the prevalence of PsA among patients with psoriasis has been estimated at between 6% and 42% (Gladman, Antoni, Mease, Clegg, & Nash, 2005). The typical demographic characteristics of PsA include an equal sex distribution, onset of joint complaints in the 30- to 50-year age group, and greater incidence in Caucasians than in African Americans and Asians. Seventy percent of PsA patients develop skin symptoms approximately 10 years before joint complications, whereas in 10%-15% of patients, joint damage precedes psoriasis. In 15%-20% of patients, arthritis and psoriasis symptoms occur simultaneously (Cassell & Kavanaugh, 2005; Gladman, 2008). Although a link between skin and joint symptoms does exist, the correlation is not directly proportional: Only 35% of patients with PsA acknowledge a relationship between the severity of their skin disease and joint activity (Gladman, 2008). Studies indicate that 40%-57% of patients with PsA will develop erosive and deforming arthritis over time (Fitzgerald, 2009). The wide range and complex nature of these PsA statistics may be attributed to the variability in the populations studied and the lack of a clear definition of PsA and understanding of PsA etiology.
Genetic, immunologic, infectious, and physical factors seem to influence PsA disease onset. Despite clustering of psoriasis and PsA within families (observed for 40% of patients; Gladman, 2008), there are substantial differences in the genetic characteristics of the two diseases (Pitzalis, 1998). PsA is not a single-gene-triggered disease, and its heritable factors are not sex-linked or sex-limited (Eastmond, 1994). Genes associated with PsA are not limited to one chromosomal locus (Eastmond, 1994; Fitzgerald, 2009; Ritchlin, 2008a, 2008b). Human leukocyte antigens, encoded on the short arm of Chromosome 6, have been associated with PsA and may be involved in antigen presentation in this disease.
Immunologic factors have also been implicated in PsA etiology. Activated plasma and synovial T-cells (predominantly CD8+ cells) express human leukocyte antigen molecules and interleukin (IL)-2 receptors (Costello, Bresnihan, O'Farrelly, & FitzGerald, 1999). They also secrete multiple proinflammatory cytokines within the synovium, including tumor necrosis factor (TNF), IL-1, and IL-2, as well as the anti-inflammatory cytokine IL-10 (Ritchlin et al., 1998). The overall result is proliferation and activation of synovial and epidermal fibroblasts, osteoclastogenesis, and resultant bony erosions (Ritchlin, Haas-Smith, Li, Hicks, & Schwarz, 2003). Recent experimental evidence also implicates the proinflammatory cytokines IL-12 and IL-23 as contributors to the pathogenesis of psoriasis. IL-12 and IL-23 share a common p40 subunit, and this subunit is overexpressed in psoriasis plaques (Fitch, Harper, Skorcheva, Kurtz, & Blauvelt, 2007). It has been hypothesized that IL-12 acts to stimulate the psoriatic phenotype by favoring the differentiation of naive TH0 cells to the TH1 phenotype characteristically seen in psoriatic skin. It has also been hypothesized that IL-23 stimulates the proliferation of TH17 cells, which in turn produce other cytokines that mediate epidermal proliferation (Nograles, Brasington, & Bowcock, 2009).
An infectious etiology has also been proposed for PsA (Muto et al., 1996). Patients with HIV demonstrate increased incidence of both psoriasis and PsA (Bruce, 2008). Physical factors such as injury have also been implicated in the development of PsA. Similar to the Koebner phenomenon in which patients may develop psoriasis at a body site of previous trauma, some patients with PsA have reported histories of trauma before the onset of their disease (Scarpa et al., 1992). The true etiology of PsA remains unknown and may involve a combination of any of the above factors. Without a clear cause of the disease, understanding the symptoms and manifestations becomes even more important in the effective diagnosis and management of PsA.
Moll and Wright (1973) were the first to define PsA as a separate and distinct entity and to classify the five types of PsA: asymmetric oligoarthritis, symmetric polyarthritis, spondyloarthropathy, arthritis mutilans, and distal arthritis (Table 1). Their definition of PsA as an inflammatory arthritis in the presence of psoriasis and lacking rheumatoid factor remains the most frequently used in current studies. Asymmetric oligoarthritis is the most common form of PsA (Marsal et al., 1999; Torre Alonso et al., 1991). This type of PsA usually involves a large joint such as an ankle or knee plus a few other joints (typically fewer than four), and unlike RA, it is not symmetric. Symmetric polyarthritis is most similar to RA because it affects multiple joints on both sides of the body simultaneously. Spondyloarthropathy, similar to ankylosing spondylitis, is characterized by stiffness of the spine or neck but can also affect the hands and feet in a fashion similar to symmetric arthritis. Sacroiliac joint involvement can be symmetric or asymmetric. Arthritis mutilans is the most severe form of PsA. It affects approximately 2% of PsA patients but is a severe, deforming, and erosive arthritis with disorganization of joints leading to digital telescoping (Bruce, 2008; Gladman 2008). This progressively destructive condition is more prevalent in women and commonly observed in patients with long-standing disease (Jones et al., 1994; Marsal et al., 1999). Another distinctive pattern is that of distal interphalangeal (DIP) involvement (Moll & Wright, 1973; Veale, Rogers, & Fitzgerald, 1994). DIP arthritis is prevalent in 1%-16% of PsA patients (Bruce, 2008; Gladman 2008) and is characterized by inflammation and stiffness specifically in the distal joints nearest the finger and toe nails.
Although the classification of PsA of Moll and Wright (1973) is widely accepted, a simpler, two-subset grouping by peripheral arthritis, or axial (spinal) disease with or without peripheral arthritis, has been increasingly adopted (Marsal et al., 1999). Many recognize the three major types of PsA proposed by Veale et al. (1994): asymmetric inflammatory oligoarthritis, symmetric polyarthritis, and psoriatic spondylitis. The newer ClASsification criteria for Psoriatic ARthritis (CASPAR) have provided measurement tools with specificity and sensitivity for both early and late disease. The CASPAR criteria identify inflammatory articular disease when the patient presents with at least three of the following features: rheumatoid factor negativity; dactylitis; juxta-articular bone formation; nail dystrophy; and current psoriasis, a history of psoriasis, or a family history of psoriasis (Taylor et al., 2006).
Despite the differences between the five classes, common disease features of PsA include morning stiffness, nail disease, and joint destruction. Distinctive radiographic features of PsA include asymmetric oligoarticular distribution, absence of periarticular osteopenia, and involvement of the DIP joints and the sacroiliac joints (Bennett, 2001). Approximately 20%-40% of patients with PsA demonstrate enthesitis, inflammatory lesions at the sites of bone attachment to tendons and ligaments (Figure 1; Cantini et al., 2001; Scarpa, 1998). Distal extremity swelling from peripheral edema, another characteristic feature of PsA, is also asymmetric and generally affects the lower limbs (Bruce, 2008). Rare manifestations of PsA include conjunctivitis, oral ulceration, urethritis, and aortic valve disease. Ocular inflammation (conjunctivitis) has been observed in up to one-third of PsA patients, and iritis has been reported in a small percentage (7%; Gladman, 2008). Nail changes, separation of nails from the nail bed, and/or pitting and mimicking of fungal infections are also frequent predictors of PsA.
Disability and reduced quality of life in PsA may be caused by both joint and skin damage. A study comparing 47 patients with RA with 47 patients with PsA revealed that, although patients with RA seemed to have greater disease severity (Sokoll & Helliwell, 2001), function and quality of life scores were similar for both groups. This suggests that the additional burden of skin disease for PsA patients compounds their impairment. Consistent with reports from psoriasis patients (Rapp, Feldman, Exum, Fleischer, & Reboussin, 1999), PsA patients also reported more emotional problems than RA patients (Husted, Gladman, Farewell, & Cook, 2001). The insidious and progressive nature of PsA and the propensity for skin symptoms to manifest before joint involvement necessitate the establishment of key diagnostic steps for dermatology professionals to detect PsA in its early stages.
Characteristic symptoms of inflammatory arthritis in PsA include pain and stiffness in affected joints, morning stiffness for more than 30 minutes, and stiffness that is accentuated by prolonged rest and improved with activity. Possible predictors of joint activity include nail dystrophy, scalp lesions, and intergluteal or perianal lesions (Wilson et al., 2009). Nail involvement has also been linked to the DIP joint disease (Furfaro, 2006). In addition to the asymmetrical joint disease, the DIP involvement (Figure 2) is thought to be a distinguishing characteristic of PsA as DIP joints are usually the first to be involved (Moll & Wright, 1973). Another common feature of PsA is dactylitis, the sausage-shaped swelling of the fingers and toes (Gladman, 2008; Table 2).
Examination of musculoskeletal structure and functional range is important in the detection of PsA (Table 2). Range of motion should be tested for all joints, especially the hands and feet. Decreased range of motion and tenderness are common in arthritic joints. Difficulty flexing fingers, forming a fist, or abducting and adducting the wrist may be indications of arthritis. Boggy or doughy swelling of joints is indicative of excessive synovial tissue or fluid in the joint space. Swelling, redness, nodules, deformity, or muscular atrophy should be noted (Gorter et al., 2002). Palpation of the feet and ankles may reveal Achilles' tendon involvement. Painful eversion and inversion of the foot in any direction are also indicative of arthritis. Arthritis of the knee may be suspected by palpation of the suprapatellar pouch on either side of the quadriceps. However, healthcare providers should be aware of other diseases that can confound PsA diagnosis.
A diagnosis of PsA requires the exclusion of other inflammatory joint diseases. Although the diagnosis of PsA can be made based on presenting history and symptoms, consideration and exclusion of other inflammatory joint diseases are important (Table 3). PsA, ankylosing spondylitis, reactive arthritis or Reiter's syndrome, and the arthritis associated with inflammatory bowel disease are all seronegative spondyloarthropathies. These diseases share a predilection for asymmetric peripheral arthritis and axial or spinal involvement. However, with the exception of PsA, these diseases do not have the silvery skin plaque component that is characteristic of psoriasis. Some of the other diseases that confound the detection of PsA are gout and osteoarthritis. Gouty arthritis, associated with hyperuricemia, has been known to present with psoriasis (Cho et al., 2001). PsA can be distinguished from gouty arthritis by the lack of hyperuricemia. The DIP involvement with Heberden's nodes in osteoarthritis may be mistaken for the DIP synovitis seen in PsA. Although it is possible to have two arthritic conditions simultaneously, the presence of swelling and erythema around the DIP joint may aid the diagnosis of PsA and distinguish it from osteoarthritis. According to the National Psoriasis Foundation, healthcare providers should suspect the presence of PsA when patients report generalized fatigue; tenderness, pain, and swelling over tendons; swollen fingers and toes; stiffness, pain, throbbing, swelling, and tenderness in one or more joints; reduced range of motion in joints; and morning stiffness and tiredness. The most common and well-established distinguishing feature of PsA is the finding of asymmetric joint involvement in an oligoarticular pattern (Gladman, 2008; Jones et al., 1994). In RA, patients present with a more symmetrical distribution of joint disease, similar to symmetric polyarthritic PsA (Helliwell, Marchesoni, Peters, Barker, & Wright, 1991; Jones et al., 1994).
Magnetic resonance imaging (MRI) is a more sensitive tool than radiography for revealing inflammatory arthritis in psoriasis patients (Offidani, Cellini, Valeri, & Giovagnoni, 1998). In a well-established disease, the presence of typical radiographic findings can be diagnostic of PsA, and, therefore, render MRI unnecessary. However, MRI seems to be useful in demonstrating entheseal changes, such as inflammation and early new bone formation, and may be useful in differentiating early spondyloarthropathy from early RA (Jevtic et al., 1995; McGonagle et al., 1998). In addition to radiographic features that distinguish PsA from RA (e.g., DIP and asymmetric joint involvement), patients with PsA also exhibit vertebral syndesmophytes (bony outgrowths from ligaments), asymmetric axial sacroiliitis (both commonly seen in spondyloarthropathies), paravertebral ossification (calcification of areas away from the edge of the vertebrae), apophyseal sclerosis, and calcification of the interspinous or anterior ligaments (Bennett, 2001). Another important feature that distinguishes PsA from RA is the absence of rheumatoid factor in 90% of PsA patients (Gladman, 1995).
Psoriatic arthritis treatment guidelines issued by the American Academy of Dermatology (Gottlieb et al., 2008) and the British Association of Dermatologists (Smith et al., 2005) decreed that, although patients with mild to moderate PsA, as defined by the percentage of the body surface area (BSA) affected, may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or intra-articular steroid injections, patients with more severe PsA should be treated with disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, as well as biologic agents. However, as clinical experience with newer biologic therapies continues to grow, these guidelines may be revised. PsA patients have suffered from an underestimation of PsA disease severity. Rheumatologists and dermatologists have been reluctant to adopt aggressive approaches in PsA management because of the misconception of PsA being a benign disease, especially when patients do not present with clinically evident joint disease. Additional treatment recommendations for PsA based on consensus between rheumatologists and dermatologists have recently been developed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (Ritchlin et al., 2008).
In clinical practice, most clinicians take these treatment guidelines into account but manage disease based on an individual's signs and symptoms of disease as well as response to therapy. As such, the use of NSAIDs is typically reserved for PsA patients with mild symptoms or as adjunct pain relievers for more moderate disease when disease-modifying therapy is necessary. NSAIDs do not have disease-modifying properties, and patients who exhibit persistent manifestations of disease or are considered to have moderate disease typically do require DMARD therapy. The addition of TNF antagonists to traditional DMARD therapy is considered for those who continue to have persistent disease or disease progression or otherwise do not tolerate traditional DMARDs. TNF antagonists may be used as a monotherapy or in combination with the traditional nonbiologic DMARDs. The combination of traditional DMARDs with anti-TNF therapy is reserved for patients with severe disease activity or ongoing joint damage and disease progression. The following sections will expand on the use of these medications in PsA.
Historically, PsA treatment has generally followed treatment paradigms for other types of inflammatory arthritis, including RA. Use of NSAIDs in PsA was thus based on typical RA treatment. Although NSAIDs are effective in treating pain and inflammation, they do not have disease-modifying activity (Mease & Goffe, 2005; Menter et al., 2008). Short-term use of corticosteroids may exacerbate skin disease (Griffiths, 1997; Salvarani, Olivieri, Cantini, Macchioni, & Boiardi, 1998). Although hydroxychloroquine has shown some modest benefit in PsA, it may elevate the risk of patients developing skin disease (Mease & Goffe, 2005; Menter et al., 2008). Some clinical benefit in PsA has been achieved with injectable gold salts, another relic from early second-line RA therapy (Bruckle, Dexel, Grasedyck, & Schattenkirchner, 1994; Palit et al., 1990). Psoralen with ultraviolet light A therapy has been shown to be useful in managing skin signs of PsA (Ritchlin et al., 2008), but does not have any effect on arthritic joints.
Jones, Crotty, and Brooks (1997) determined via a meta-analysis of 12 clinical trials that, of several available treatments, only intramuscular methotrexate and oral sulfasalazine were effective in the treatment of PsA. Of these, methotrexate, another therapeutic agent borrowed from the RA treatment arsenal, showed the most promise. Methotrexate was traditionally an anticancer agent but was adopted for use in connective tissue diseases such as RA in the 1980s. As early as 1984, controlled trials with methotrexate demonstrated some benefit for patients' joint symptoms, such as improvement in tender and swollen joint counts, pain, and functional scores, as well as improvement in morning stiffness and reduction in plasma erythrocyte sedimentation rates (Mease & Goffe, 2005). Skin signs were also alleviated, as evidenced by an improvement in the Physician's Global Assessment scores (Mease & Goffe, 2005). Thus, methotrexate has been a reasonable and expected first-line therapy for PsA, owing to its low cost and long history of use. Even so, only 37% of patients demonstrated no evidence of active synovitis, and only 58% had fewer than four active joints after 34 months of treatment with methotrexate at 11.2 mg/week (Espinoza et al., 1992). Also, although methotrexate provides symptomatic relief, it does not adequately control underlying radiographic progression (Abu-Shakra et al., 1995) and, in the long run, does not substantially improve patients' quality of life. Despite its modest efficacy, methotrexate is used for the chronic management of PsA. Although effective in most patients, the potential risks of hepatotoxicity, drug interactions, myelosuppression, pneumonitis, and teratogenicity associated with methotrexate in the psoriasis and PsA populations limits its usefulness in many clinical cases (Menter et al., 2008). Long-term use of methotrexate should be managed to the American College of Rheumatology (ACR) guidelines to minimize potential toxicities (Lindsay et al., 2009).
Several studies have compared sulfasalazine with placebo and have shown some reduction in signs and symptoms of joint disease (Clegg et al., 1996; Combe et al., 1996; Jones, Crotty, & Brooks, 1997) but no advantage in preventing joint damage (Rahman, Gladman, Cook, Zhou, & Young, 1998). Sulfasalazine has been modestly effective in the treatment of PsA, with statistically significant improvements in Psoriatic Arthritis Response Criteria versus placebo at 2 g/day (Clegg, Reda, & Abdellatif, 1999; Clegg et al., 1996) and significant improvement in PsA signs and symptoms at 3 g/day (Dougados et al., 1995). Cyclosporine, a staple in the treatment of psoriasis, has also been evaluated in the treatment of PsA and was found to be more effective for skin disease than for joint symptoms (Mahrle et al., 1996). A comparative trial of cyclosporine and methotrexate for the treatment of PsA demonstrated improvement in several measurements of joint disease activity for both compounds (Spadaro et al., 1995). Although it has been shown to have efficacy similar to methotrexate (Spadaro et al., 1995), cyclosporine is limited by potential renal toxicity, hypertension, risk of drug-drug interactions, and malignancy. Further, a significant number of patients receiving cyclosporine over the long-term (3-5 years) will develop some degree of glomerulosclerosis (scarring of the kidney's blood vessels). Therefore, published U.S. guidelines limit the use of cyclosporine to 1 year. Furthermore, in July 2009, the Food and Drug Administration (FDA) began requiring manufacturers of cyclosporine products to update their labeling to reflect that immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections (e.g., BK-virus-associated nephropathy). Leflunomide has been examined as PsA therapy and has provided statistically significant improvements of skin lesions. However, a greater discontinuation rate due to toxicity was observed for leflunomide-treated patients compared with other DMARD-treated patients (Malesci, Tirri, Buono, & La Montagna, 2007).
Increased understanding of the pathogenesis of inflammatory joint disease has yielded new therapies that target the inflammatory cascade and prevent disease progression. TNF, a proinflammatory cytokine, is known to play an important role in the pathogenesis of arthritis. Elevated concentrations of TNF have been found in the joint synovium and in the psoriatic lesions of patients with PsA (Ettehadi, Greaves, Wallach, Aderka, & Camp, 1994; Terajima, Higaki, Igarashi, Nogita, & Kawashima, 1998). A comparison of TNF inhibitors approved for the treatment of PsA is provided in Table 4. Although a head-to-head study has not been performed to examine differences in efficacy and safety between the three TNF antagonists, it is evident that the monoclonal antibodies adalimumab and infliximab may have better ACR70 and better skin efficacy outcomes than etanercept. Other cytokines, such as IL-12, IL-17, and IL-23, are also believed to play a pathogenic role in PsA and other inflammatory autoimmune disorders (Fitch, Harper, Skorcheva, Kurtz, & Blauvelt, 2007). This is supported by the finding of increased concentrations of the shared p40 subunit of IL-12 and IL-23 in the skin and synovial fluid of patients with PsA (Nograles, Brasington, & Bowcock, 2009). New biologic therapies targeting IL-12 and IL-23 are emerging.
Adalimumab, a fully human, anti-TNF monoclonal antibody, has been shown to be very effective in the treatment of PsA, with and without methotrexate, and was approved by the FDA for the treatment of the disease in 2005. It is self-administered at a dosage of 40 mg every other week. Two Phase III, randomized, double-blind, placebo-controlled, multicenter trials in patients with moderate to severe PsA (>=3 swollen and >=3 tender joints) demonstrated that adalimumab was highly efficacious for patients who had an inadequate response to NSAIDs (ADalimumab Effectiveness in Psoriatic Arthritis Trial [ADEPT]; Mease et al., 2005) and in those who had an inadequate response to DMARDs (Genovese et al., 2007). These adalimumab trials had very stringent efficacy criteria compared with those of other biologic trials. In ADEPT, 58% of patients treated with adalimumab (40 mg every other week) achieved ACR20 at Week 12 versus 14% of placebo-treated patients (p < .001). This improvement was maintained through 24 weeks of adalimumab therapy. The smaller study of patients who had failed DMARD therapy mimicked the efficacy outcomes of ADEPT. Adalimumab-treated patients demonstrated a minimal change in radiographic progression at 24 weeks, and control of joint disease was maintained through 24 weeks of treatment (Gladman et al., 2007), thereby preventing further destruction of the joints. Skin disease was also well managed with adalimumab treatment, with 75% of patients achieving Psoriasis Area and Severity Index (PASI) 50, 59% achieving PASI 75, and 42% achieving PASI 90 improvement in psoriasis (p < .001 compared with placebo) at Week 24. These clinical responses and inhibition of radiographic progression were maintained through 48 weeks (Gladman et al., 2007) and 2 years (Mease et al., 2008). The impact on patients' quality of life was also significantly improved with adalimumab treatment versus placebo.
Etanercept is a soluble, TNF-receptor fusion protein, administered for PsA at a dosage of 25 mg twice weekly or 50 mg weekly, which binds soluble and membrane-bound TNF and lymphotoxin. It was approved by the FDA for treatment of PsA in 2002 and has been shown to reduce the signs and symptoms, prevent joint destruction, and improve patients' quality of life. Two placebo-controlled trials in PsA demonstrated that etanercept provided significant benefit to patients with PsA and significantly reduced the signs and symptoms of joint disease compared with the placebo-treated group (Mease et al., 2000; Mease et al., 2004). Etanercept was effective as a monotherapy or in combination with methotrexate (Mease et al., 2000). At Week 12 of one placebo-controlled trial, 87% of etanercept-treated (25 mg twice weekly) patients achieved the primary end-point (improvements in tender and swollen joint counts by >=30% and Physician's or Patient Global Assessments by at least 1 point), compared with 23% (p < .001) of the placebo group. Skin improvements, as assessed by PASI 75, evaluated in those patients that had >=3% BSA involvement at baseline (n = 38), were observed for 26% of etanercept-treated patients and for none of the placebo-treated patients after 12 weeks of treatment. In the second, larger, multicenter study of 205 patients, etanercept (25 mg twice weekly) was administered, with or without concomitant methotrexate, in an initial 24-week blinded phase followed by an unblinded, 48-week, open-label extension study. At Week 24, 59% of etanercept-treated patients, compared with 15% of placebo-treated patients, achieved significant improvements in their joint symptoms. At Week 24, 23% achieved at least a PASI 75 response in improvement of psoriasis symptoms, compared with no improvement in the placebo group (p < .001). Etanercept treatment also controlled the radiographic progression of joint disease (Mease et al., 2004). A third, randomized, multicenter study evaluated the efficacy of etanercept during 12 weeks (50 mg twice weekly or 50 mg once weekly) in patients with both psoriasis and PsA (Sterry et al., 2008). Etanercept provided greater benefit in the skin symptoms with the twice-weekly dosage. At Week 12, 55% of patients treated with etanercept twice weekly achieved a PASI 75 response versus 36% of patients treated with etanercept once weekly. Although the skin response varied by dosage, joint manifestations showed similar improvements with both regimens.
Infliximab is a chimeric (human-mouse) IgG1 monoclonal antibody that targets soluble and membrane-bound TNF. It is administered via intravenous infusion at a dosage of 5 mg/kg at Weeks 0, 2, and 6 and every 8 weeks thereafter. Two placebo-controlled trials examined the effectiveness of infliximab against PsA. At Week 16 of the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT), 65% and 68% of infliximab-treated patients achieved ACR20 and PASI 75, respectively, compared with 10% and 0% of the placebo-treated patients (p < .001). Enthesitis and dactylitis also improved with infliximab treatment. In IMPACT 2, infliximab provided benefit to patients with PsA, reducing joint and skin symptoms at a degree similar to that observed in the IMPACT study (Antoni et al., 2005). No radiographic progression was seen after 50 weeks of infliximab treatment. Infliximab was also approved by the FDA for the treatment of PsA in 2002.
Ustekinumab is a human monoclonal antibody that inhibits receptor binding of IL-12 and IL-23. Clinical findings suggest that these cytokines may play an important role in the pathogenesis of PsA (Ribbens et al., 2000; Ritchlin et al., 1998). A Phase II study evaluated the efficacy and safety of ustekinumab (90 or 63 mg) in patients with PsA (Gottlieb et al., 2009). At Week 12, 42% of ustekinumab-treated patients compared with 14% of placebo-treated patients achieved ACR20. Of the 63 ustekinumab-treated patients with >3% BSA affected by psoriasis, 52% achieved a PASI 75 response at Week 12 versus 5% of 55 placebo-treated patients with skin involvement. Ustekinumab has also been shown to be effective in the treatment of moderate to severe plaque psoriasis in two Phase III trials, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of CNTO 1275 in the treatment of subjects with moderate to severe plaque-type psoriasis (PHOENIX 1 and PHOENIX 2) (Leonardi et al., 2008; Papp et al., 2008). Currently, ustekinumab is not yet approved for the treatment of psoriasis or PsA in the United States but was approved in late 2008 and early 2009 for the treatment of moderate to severe plaque psoriasis in Canada and the European Union, respectively.
Efficacy and safety evaluations of several RA and PsA therapies, including parenteral gold, methotrexate, and sulfasalazine, revealed that although efficacy was similar for all three drugs for these two diseases, toxicity rates were greater among PsA patients (Ujfalussy, Koo, Sesztak, & Gergely, 2003). Adverse effects, such as rash and hematologic disorders following treatment with gold salts, and infections from methotrexate therapy, may limit the applicability of these agents in PsA treatment.
With any TNF antagonist, there is an inherent risk of serious adverse events, such as increased susceptibility to infections, and risk of heart failure, lymphomas, lupus, and demyelinating diseases. Compared with the clinical trial experience with methotrexate and sulfasalazine, the clinical trial experience in PsA studies of TNF antagonists is broad, and there does not appear to be any evidence of cumulative organ-specific toxicity. Increased incidence of reactivation of latent tuberculosis (TB) infection has been reported with all TNF inhibitors (Bresnihan & Cunnane, 2003; Keane et al., 2001; Lebwohl, 2002). Patients should be screened for TB before commencing biologic therapy (Centers for Disease Control and Prevention, 2004). Annual TB testing during anti-TNF therapy has also been suggested. In addition, patients should be monitored for signs and symptoms of TB throughout TNF antagonist therapy.
Other adverse events have also been reported with anti-TNF agents. Infliximab has been associated with malignancies such as lymphomas, breast carcinomas, skin tumors, and rectal cancer. Infliximab-associated neurological disorders include demyelination, optic neuritis, and peripheral neuropathy (Bresnihan & Cunnane, 2003). Etanercept has been associated with vasculitis, diabetes mellitus, and demyelination (Bresnihan & Cunnane, 2003). Demyelinating disorders and malignancies such as lymphomas have been associated with adalimumab therapy as well, but at least as of April 2007, the incidence had not been found to be statistically significant (Burmester, Mease, Dijikmans, Gordon, Lovell, Panaccione, et al., 2009).
Fortunately, PsA is increasingly recognized as a common inflammatory arthropathy that may cause progressive joint damage and disability. Dermatology professionals are the first key link in the early identification of patients with PsA. With earlier detection and diagnosis, patients with PsA may be spared pain, disability, and joint damage and instead enjoy a greater quality of life through early management of psoriatic disease. All dermatology professionals should learn to actively screen for and identify PsA as they will be regularly monitoring skin disease progression and educating patients on their disease states. Once PsA is identified, or suspected, cooperation between dermatology and rheumatology healthcare providers can result in the effective management of the varying skin and joint symptoms of PsA. Newer therapeutic agents, such as TNF antagonists, offer the potential for greatly improved efficacy. Rather than propagating a palliative treatment strategy, healthcare providers should work together in an interdisciplinary approach to provide patients with therapeutic options that prevent structural damage and deterioration of quality of life.
The authors thank Teresa R. Brtva, PhD, of Arbor Communications, Inc., and Michael A. Nissen, ELS, of Abbott Laboratories for editorial assistance in the development and revision of this article. This support was funded by Abbott.
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