Patient Profiles in Psoriatic Disease: A Case-Based Approach

By Wiatrowski, Mary Furfaro, Nicole

Psoriasis and psoriatic arthritis are related conditions that can have numerous untoward consequences. Moreover, appropriate management of these conditions can be challenging, as each affected patient has unique needs that must be addressed. With that in mind, the authors discuss three reallife cases, highlighting principles that may facilitate the effective case-by-case management of psoriatic disease. Psoriasis is a common dermatologic disorder, affecting an estimated 5.8 to 7.5 million U.S. residents (National Institute of Arthritis and Musculoskeletal and Skin Diseases, 2003). In a broad sense, T cell-induced skin inflammation and keratinocyte hyperproliferation are the central features of psoriasis (de Rie, Goedkoop, & Bos, 2004), although there may be substantial variability from case to case in terms of how these features are clinically presented. Nonetheless, while there is considerable heterogeneity with regard to the possible clinical presentations of psoriasis, one clinical variant of the disease, known as plaque psoriasis, predominates, accounting for more than 80% of psoriasis cases overall (Biondi, Scarpa, Pucino, & Oriente, 1989). Sharply demarcated, scaly, inflamed, red skin lesions, which preferentially arise on the extensor surfaces of the body, represent the primary clinical manifestation of plaque psoriasis. Furthermore, some affected patients may, as an additional feature of plaque psoriasis, exhibit certain forms of nail dystrophy, such as pitting, staining, or onycholysis (Griffiths et al., 2007).

Due to its chronic, inflammatory nature, psoriasis can have significant detrimental effects (Krueger et al., 2001). With regard to physical effects, 94%, 79%, and 71% of the 17,488 respondents to a 1998 mail survey of the patient membership of the National Psoriasis Foundation (NPF) reported experiencing scaling, itchiness, and redness of the skin, respectively, as a result of their psoriasis, while various other physical symptoms were reported by smaller but still substantial percentages of respondents. Moreover, a phone survey associated with the 1998 NPF mail survey provided evidence that psoriasis can also have a negative impact on emotional well-being. In that phone survey, which involved a random sample of 502 patients with severe psoriasis who had participated in the 1998 NPF mail survey, it was found that among respondents 18 to 34 years old, 81% felt embarrassment upon having their psoriasis viewed by others, while 75% experienced feelings of unattractiveness, and 54% experienced feelings of depression in association with their psoriasis.

Aside from experiencing psoriasis-related losses in the physical and psychological domains, some patients with psoriasis may encounter further harm as a result of psoriatic arthritis (PsA), an inflammatory joint condition associated with psoriasis. Estimates of PsA prevalence among patients with psoriasis vary widely from study to study, ranging from 7% to 42% (Mease, 2004a). Nonetheless, regardless of the exact prevalence, it is clear that PsA can have consequences that are quite serious, extending beyond the development of joint pain and swelling. In fact, prospective studies have found that 43% to 57% of patients with PsA exhibit joint deformities or radiographically detectable joint erosions. Furthermore, the same studies found that severe physical disability is evident in 11% to 19% of all PsA cases, suggesting that PsA- related joint damage can lead to significant functional impairment (Gladman, Shuckett, Russell, Thorne, & Schachter, 1987; Torre Alonso et al., 1991).

Given the untoward consequences associated with psoriatic disease, it is critical that psoriasis and PsA be managed appropriately, with a focus on clinical, psychological, and functional outcomes. Appropriate management can be challenging, however, as each patient has unique features and needs that have a bearing on the suitability of available disease management interventions. Thus, for the sake of optimizing outcomes in psoriatic disease, a case-bycase approach is warranted. With that in mind, this Supplement, through discussion of three real-life cases, seeks to emphasize key principles that may aid clinicians in the case-by-case management of psoriatic disease.

Case 1: The Need for Early and Aggressive Intervention

Hugh is in his mid 70s. In addition to having a long personal history of psoriasis, he has had PsA for nearly a decade. In the early stages following its clinical onset, Hugh’s PsA began to take a deforming course. Most notably, a tendon deformity developed in the fifth toe of Hugh’s right foot, and bony enlargements, which in several cases ultimately led to fixed deformities (specifically, flexion contractures) of the fingers, developed at multiple joints in both of Hugh’s hands.

In recent years, Hugh has been receiving monotherapy with a tumor necrosis factor-alpha (TNF-alpha) antagonist, and although he continues to show the deformities that were present prior to the start of TNF-alpha antagonist therapy, he has not since developed any new deformities, and TNF-alpha antagonist therapy has been largely effective in controlling his psoriatic skin and joint symptoms. Thus, at present, Hugh exhibits only minor arthritic swelling at various sites, along with limited psoriatic inflammation of the skin and a small amount of psoriatic nail involvement.

Case Discussion

Hugh’s case highlights the importance of treating PsA in a prompt and aggressive manner. Had Hugh begun treatment with a disease- modifying agent (an agent capable of slowing the progression of bone and joint damage in PsA) prior to the emergence of any PsA-related deformities, the subsequent development of such deformities may have been prevented or delayed, allowing Hugh to maintain a higher level of physical function and better quality of life for a longer period of time. It is therefore unfortunate that the onset of Hugh’s PsA and the emergence of his PsA-related deformities occurred years before any diseasemodifying therapies for PsA had been developed.

For patients who are diagnosed with PsA in the present day, diseasemodifying options for treatment of the disease from its earliest stages onward do exist. Currently available disease- modifying therapies act by inhibiting the activity of TNF-alpha, a T helper type 1 cytokine that is found at elevated levels in synovial tissue and synovial fluid in patients with PsA and in lesional skin in patients with psoriasis (Bonifati et al., 1994; Partsch et al., 1997; Ritchlin et al., 1998). TNF-alpha is thought to take part in the destruction of bone and joints in PsA by (a) inducing the release of bone and joint-eroding effector molecules by cells in or near joint spaces and (b) up-regulating the body’s production of osteoclasts, cells that mediate the degradation of bone tissue (Mease, 2004b). Moreover, TNF-alpha appears to contribute to psoriatic skin and joint phenotypes in other ways as well; for example, by promoting the migration of activated T cells to the skin and by directly mediating inflammation of the skin and joints (de Rie et al., 2004; Mease, 2004b).

At present, three biologic TNF-alpha antagonists – the fusion protein construct etanercept, the chimeric murine/human monoclonal antibody infliximab, and the human monoclonal antibody adalimumab – are known, based on phase 3 testing, to be effective in inhibiting the progression of PsA-related structural damage (Mease et al., 2004; Mease et al., 2005; van der Heijde et al., 2006). The demonstrated diseasemodifying efficacy of TNF-alpha antagonist therapy is highly noteworthy, as no other type of treatment is known to have disease-modifying effects in PsA. However, TNF-alpha antagonist therapy is also efficacious in treating other aspects of psoriatic disease, as would be expected given the apparent involvement of TNF-alpha in psoriatic disease processes other than the destruction of bone and joints. In particular, phase 3 clinical trials have found that each of the three available TNF-alpha antagonists is superior to placebo in eliciting clinically significant reductions in overall arthritic activity in patients with PsA (see Figure 1) (Antoni et al., 2005; Mease et al., 2004; Mease et al., 2005; Siegel, 2002). In addition, each available TNF- alpha antagonist exhibits efficacy in producing clinically significant reductions in the severity of cutaneous symptoms in patients with moderate-to-severe plaque psoriasis (see Figure 2) (Leonardi et al., 2003; menter, Feldman et al., 2007; Menter, Papp, Leonardi, & Frevert, 2007; Papp et al., 2005; Reich et al., 2005; Saurat et al., 2000; Tyring et al., 2007). This was most recently shown in the Randomized Controlled Evaluation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis Trial (REVEAL), a phase 3 study involving over 1,200 patients (Menter, Papp et al., 2007).

With the TNF-alpha antagonists now established as effective options for inhibiting the progression of bone and joint damage in PsA, prompt detection of PsA stands as a key consideration for ensuring that affected patients can begin receiving disease- modifying anti-TNF-alpha therapy at the earliest possible point in the natural course of the disease. Dermatology professionals are ideally suited to participate in early detection efforts, given the relative timing with which the onset of psoriasis and the onset of PsA occur. Observational cohort data indicate that for approximately 70% of all patients with PsA, the clinical onset of the disease follows the clinical onset of psoriasis by 1 year or more (Gladman et al., 1987), meaning that most patients who develop PsA will, at some point before PsA onset, visit a dermatology office for treatment of psoriasis. Thus, by screening for arthritic signs in patients seeking care for psoriasis, dermatology professionals can serve as a first line in the detection of PsA. For dermatology professionals, effective participation in PsA screening efforts is contingent upon having a sound understanding of the clinical signs of PsA. Foremost among these signs is arthritic inflammation, which is typically the principal feature of PsA. Most patients with PsA experience inflammation predominantly in the joints of the hands and/ or feet. However, a nontrivial percentage of affected patients exhibit arthritic inflammation at other sites (for example, spinal joints, sacroiliac joints) as their primary disease feature. Symptoms that may arise in association with PsA-related arthritic inflammation include joint pain, swelling, and tenderness. Furthermore, arthritic inflammation in PsA may be indicated by the presence of joint stiffness, which is most pronounced during the morning hours (immediately after waking) and resolves gradually thereafter with physical activity (Gladman, 2004).

While arthritic inflammation is generally the central feature of PsA, it is by no means the only form of musculoskeletal inflammation that may develop in association with the disease. Dactylitis (widespread inflammation of the joints and tendons in a given digit) is also common, occurring in one third of all patients with PsA (Gladman et al., 1987), while enthesitis (inflammation at a site of tendon, ligament, or joint capsule fiber insertion into bone) is estimated to be clinically observable in 19% of all PsA cases (Scarpa, Ames, della Valle, Lubrano, & Oriente, 1994). In terms of symptomatology, the most prominent symptom of dactylitis is diffuse swelling of the affected digit; however, pain and tenderness are often evident in dactylitic digits as well. Likewise, enthesitis may be accompanied by pain, tenderness, or soreness at the involved site, which in PsA is typically an entheseal site in the area of the chest, elbow, knee, heel, or sole of the foot. An important point to note regarding the diagnostic significance of dactylitis and enthesitis is that neither feature is seen with any regularity in other common forms of arthritis (for example, osteoarthritis, rheumatoid arthritis [RA]), and so the finding of either feature in a patient with psoriasis is strongly suggestive of PsA (Mease & Goffe, 2005).

Certain nonmusculoskeletal signs may also have relevance with regard to PsA screening. One such sign is nail involvement, as the large majority of patients with PsA – more than 80% (Gladman et al., 1987), as compared with 46% of patients who have psoriasis alone (Gladman, Anhorn, Schachter, & Mervart, 1986) – have psoriatic nail lesions of some type. Possible nonmusculoskeletal signs of PsA are not limited to the nails, however, as eye inflammation and various other inflammatory features (for example, stomatitis, urethritis) may also be present in PsA. Moreover, it is not uncommon for PsA to be accompanied by chronic fatigue, which in some cases may be quite severe (Gladman, 2004; Mease & Goffe, 2005).

Summary

Psoriatic arthritis can cause progressive damage to bone and joints, and therefore, early treatment of PsA with an effective, disease-modifying agent is essential. Patients found to have PsA in the present day have access to disease-modifying agents from the time of diagnosis onward; thus, the promptness with which disease- modifying therapy can be initiated is limited only by how quickly (following the onset of PsA pathogenesis) PsA can be diagnosed. As a result, early detection of PsA has become critical for optimizing patient outcomes.

Dermatology professionals are well positioned to take an active role in the early detection of PsA, as the relative timing of psoriasis onset and PsA onset is such that patients who develop PsA will typically be seen at a dermatology office for the treatment of their psoriasis at some point before the emergence of PsA. Consequently, by gaining familiarity with the features of PsA and applying that familiarity in screening for arthritic signs in patients with psoriasis, dermatology professionals can play a key part in ensuring that PsA is diagnosed and treated in a timely fashion.

Case 2: Transitioning From Traditional to Biologic Therapy

Kathie is in her mid 50s. She has had psoriasis since childhood, although her psoriatic skin symptoms have grown less severe over the course of her life. Nearly 5 years ago, Kathie began to report pain in her chest. Subsequent cardiac testing revealed no signs of heart disease, and so Kathie was referred to a rheumatology clinic, where it was found that her pain was originating from the sternocostal joints. Shortly thereafter, Kathie also developed swelling in several toes, and she began to have pain in her heels and toes, with this pain being most severe upon waking each morning. Kathie’s chest pain and foot pain both led to significant functional limitations, the former leaving her unable to dress independently and the latter making it difficult for her to walk.

On the basis of her symptoms (chest pain [which was consistent with enthesitis of the sternocostal ligaments], swelling of the toes [presumably a manifestation of dactylitis], and morning stiffness), as well as her history of psoriasis, Kathie was diagnosed with PsA. Following diagnosis, she was first treated with methotrexate (MTX), and she experienced a partial response as a result. However, she was eventually forced to discontinue MTX due to treatment-related malaise. Kathie was then switched to treatment with a TNF-alpha antagonist, which proved to be highly effective, leading to near- complete resolution of her chest and foot pain and to a decrease in the swelling of her toes. Since then, she has continued to receive TNF-alpha antagonist therapy, as her favorable therapeutic response has persisted, and no treatment-related tolerability problems have arisen.

Case Discussion

Kathie’s case underscores the point that for patients with psoriatic disease, benefit may be realized through switching from traditional systemic therapy to systemic biologic therapy. Upon being diagnosed with PsA, Kathie was treated with MTX, a traditional systemic agent, and although MTX induced a partial response, it was poorly tolerated. Thus, Kathie made the transition to treatment with a systemic biologic agent, which ultimately produced a more complete response and was better tolerated than MTX.

Of late, changes in the psoriatic disease treatment paradigm have expanded opportunities for the use of systemic therapies in general. For example, until recently, the prevailing psoriasis treatment model stated that for any given patient, treatment with more aggressive therapies was appropriate only if less-aggressive therapies had first been tried and found to be inadequate. Thus, topical therapy was recommended as a first-line treatment option for every affected patient, with phototherapy reserved for use in the event that topical therapy was unsuccessful, and systemic therapy reserved for use in the event that phototherapy was unsuccessful as well. Over time, however, it became clear that this stepwise model was unsuitable for more severely affected patients, especially in light of findings indicating that in the era in which the model was widely used, frustration with treatment and the desire for more aggressive treatment were relatively common among patients with severe psoriasis (Krueger et al., 2001). As a result, newer guidelines have called for more aggressive treatment of comparatively severe cases of psoriatic disease. In particular, the guidelines released by the American Academy of Dermatology (AAD) in 2003 state that systemic therapy should be considered an appropriate first-line option for the treatment of moderate-to-severe psoriasis and that systemic therapy may also be warranted for first-line treatment of PsA, no matter how severe the accompanying psoriatic skin disease (Callen et al., 2003).

As has been alluded to, systemic psoriatic disease therapies such as those described in the AAD guidelines can be divided into two categories: traditional therapies and biologic therapies. Commonly used agents in the former category include MTX, cyclosporine, and acitretin. Of those, MTX and cyclosporine appear to be effective in treating the symptoms of psoriasis and (at least to some extent) in treating the symptoms of PsA (Griffiths, Clark, Chalmers, Li Wan, & Williams, 2000; Soriano & McHugh, 2006). However, MTX is regarded as having a more favorable overall risk-benefit profile and is therefore widely considered to be the “gold standard” among traditional agents. In the category of biologic medications for psoriatic disease, the TNF-alpha antagonists etanercept, infliximab, and adalimumab are joined by two other agents – alefacept and efalizumab – both of which act by directly blocking the participation of T cells in certain pathways implicated in psoriasis pathogenesis (Astellas Pharma U.S., Inc., 2006; Genentech, Inc., 2005). Although no head-tohead comparisons of biologic anti-TNF- alpha therapy with T cell-targeted biologic therapy have been performed, examination of response rates across separate trials, which have generally involved similar patient populations and have been performed according to similar protocols (see Table 1), suggests that over the short term (10-16 weeks), existing TNF-alpha antagonists may be more likely than existing T cell-targeted biologics to yield favorable responses in patients with moderate-to- severe psoriasis (Dubertret et al., 2006; Gordon et al., 2003; Krueger et al., 2002; Lebwohl, Christophers et al., 2003; Lebwohl, Tyring et al., 2003; Leonardi et al., 2003; Leonardi et al., 2005; Menter, Papp et al., 2007; Menter, Feldman et al., 2007; Papp et al., 2005; Reich et al., 2005; Saurat et al., 2006; Tyring et al., 2007), and longer-term data indicate that while cutaneous responses achieved in the short term with TNF-alpha antagonist therapy may subsequently be lost by a limited subset of patients, such responses are, in general, well maintained over time (Menter, Papp et al., 2007; Menter, Feldman et al., 2007; Reich et al., 2005; Sterry, 2004; Tyring et al., 2007). Furthermore, among available biologic agents, only the TNF-alpha antagonists have confirmed efficacy in the treatment of PsA (Antoni et al., 2005; Mease et al., 2004; Mease et al., 2005; Siegel, 2002; van der Heijde et al., 2006). In modern practice, clinicians often turn to the traditional agent MTX for the initial treatment of patients with PsA and/or moderate-to-severe psoriasis. Nonetheless, given certain aspects of the risk-benefit profile of MTX, it may frequently be the case that patients receiving MTX therapy can benefit from switching to treatment with a biologic TNF-alpha antagonist. The decision to switch a patient from MTX therapy to TNF-alpha antagonist therapy may often be driven by concerns regarding treatment tolerability. Common side effects that may limit the tolerability of MTX include malaise, headache, and gastrointestinal disturbance (Roenigk, Jr., Auerbach, Maibach, Weinstein, & Lebwohl, 1998). Also potentially relevant in terms of the utility of switching therapies is treatment safety, as MTX has cumulative hepatotoxic effects, which may detract from its suitability for longterm use; cumulative MTX-induced hepatotoxicity can be especially problematic for alcohol users, since alcohol is known to exacerbate the effects of MTX on the liver (DAVA Pharmaceuticals, Inc., 2003; West, 1997). Other safety considerations that may have a bearing on the usefulness of switching treatments include teratogenicity, as the use of MTX to treat psoriasis is (due to teratogenicity concerns) contraindicated during pregnancy (DAVA Pharmaceuticals, Inc., 2003), and bone marrow toxicity, as methotrexate use carries a small but appreciable risk of pancytopenia, which may in certain cases be life-threatening (Gutierrez-Urena, Molina, Garcia, Cuellar, & Espinoza, 1996).

Overall, then, it appears that certain patients may be able to achieve improved tolerability and/or safety outcomes by switching from MTX therapy to TNF-alpha antagonist therapy, as available data indicate that TNF-alpha antagonist therapy is well tolerated in general and that serious adverse events associated with TNF-alpha antagonist use are rare (Keystone, 2005). However, tolerability and safety issues aside, support also exists for the idea that the transition from MTX therapy to TNF-alpha antagonist therapy can lead to gains in efficacy. For instance, MTX appears to be effective only in treating the symptoms of PsA (Soriano & McHugh, 2006), whereas all three TNF-alpha antagonists exhibit both symptomatic and disease- modifying efficacy in PsA (Antoni et al., 2005; Mease et al., 2004; Mease et al., 2005; van der Heijde et al., 2006), and therefore, switching from MTXtherapy to TNF-alpha antagonist therapy may be beneficial from an efficacy standpoint for patients with PsA. Moreover, a recent phase 3 trial has provided the first direct evidence of the superiority of a TNF-alpha antagonist over MTX in treating psoriatic skin disease. In that trial (the Comparative study of Humira vs. Methotrexate vs. Placebo in Psoriasis Patients [CHAMPION]), which evaluated the effectiveness and safety of adalimumab in patients with moderate-to-severe plaque psoriasis, adalimumab was both well tolerated and significantly more effective than either MTX or placebo in producing favorable cutaneous responses over a 16-week period (see Figure 3) (Saurat et al., 2006).

Summary

With the emergence of a new psoriatic disease treatment paradigm in recent years, systemic medications have come to be recognized as appropriate options for the first-line treatment of more serious cases of psoriatic disease. Of the systemic treatment options available, the traditional agent MTX is a relatively common choice for the initial treatment of PsA and/or moderate-tosevere psoriasis. Despite its common use, however, MTX has potential limitations with regard to tolerability, safety, and efficacy. Therefore, certain patients who receive MTX for their psoriatic disease – patients such as Kathie, who experienced intolerable side effects and had only a partial therapeutic response while taking MTX – may benefit from switching to treatment with a TNF-alpha antagonist, as TNF-alpha antagonist therapy is well tolerated and adequately safe, in addition to having an efficacy profile that may in some ways be superior to that of MTX.

Case 3: Optimizing Treatment Outcomes

Carl is in his mid 40s. For several years, he has had psoriasis, which has been characterized by the appearance of psoriatic plaques on the elbows, knees, and eyebrows. Then, almost 1 year ago, Carl began to experience severe foot pain and swelling, along with pain in the right sacroiliac region. Carl’s foot pain in particular had a dramatic effect on his functional abilities, to the point where he regularly had difficulty walking and was even forced to avoid standing for 5 to 6 full days out of every month.

Given Carl’s history of psoriasis, his foot symptoms and sacroiliac pain were taken to be indicative of PsA. Methotrexate was prescribed for the initial treatment of Carl’s PsA; however, after each of his first two MTX doses, Carl experienced severe abdominal pain and nausea. Thus, the decision was made to discontinue MTX and switch to treatment with a TNF-alpha antagonist. TNF-alpha antagonist therapy was initially effective in controlling Carl’s skin and joint symptoms, but after having responded favorably for several months, Carl had to temporarily halt treatment so that he could receive vaccinations in preparation for an overseas vacation. Upon temporary cessation of TNF-alphaantagonist therapy, Carl’s psoriatic skin and joint symptoms flared, and when therapy was reinstated weeks later, it was not effective in reestablishing a therapeutic response. Carl was therefore switched to treatment with a different TNF-alpha antagonist, which led to rapid improvement of his symptoms and has since been successful in maintaining symptom control.

Case Discussion

In addition to reemphasizing the possible benefits of switching from MTX therapy to TNF-alpha antagonist therapy, Carl’s case highlights the key role that the treating clinician can play in ensuring the optimal use of TNF-alpha antagonist therapy. Of particular relevance is the decision to halt TNF-alpha antagonist therapy in the period leading up to and immediately following vaccination. This decision was made with the aim of reducing Carl’s risk of developing an opportunistic infection through exposure to pathogens contained in live vaccines. This decision illustrates the need for clinicians to be aware of the safety considerations associated with TNF-alpha antagonist use, so as to minimize the risk of serious, treatment-related adverse events for patients receiving TNF-alpha antagonist therapy.

Overall, the incidence of serious, treatment-related adverse events in patients receiving TNF-alpha antagonist therapy is rare (Keystone, 2005). However, certain serious adverse events may exhibit some type of association with TNF-alpha antagonist use. For example, due to the involvement of TNF-alpha in normal immune function, TNF-alpha blockade has been putatively linked to the occurrence of serious infection. In addition, it is thought that there may be a specific link between TNF-alpha therapy and the reactivation of tuberculosis (TB). As animal data suggest, TNF- alpha takes part in processes that, in persons infected with Mycobacterium tuberculosis (MTB), are responsible for preventing the spread of MTB throughout the body and thus keeping the infection in a latent state (Algood, Chan, & Flynn, 2003).

With regard to clinical evidence of an association between TNF- alpha antagonist use and TB, treatmentemergent TB has been documented in rare cases in patients receiving TNF-alpha antagonist therapy (Keystone, 2005). The TB risk conferred by TNF-alpha antagonist therapy has not been reliably enumerated, however, because background rates of TB incidence in the disease settings in which TNF-alpha antagonist therapy is used are not well established. In any event, there is a consensus that TNF-alpha antagonist use does, to some degree, place patients at increased risk for the reactivation of TB (Hochberg, Lebwohl, Plevy, Hobbs, & Yocum, 2005). Less clear is whether TNF-alpha blockade is linked to an increased incidence of non-TB-related serious infections, as conflicting findings regarding the overall risk of serious infection among patients receiving TNF-alpha antagonist therapy have been reported (Bongartz et al., 2006; Lebwohl, Gottlieb, Wallis, Jahreis, & Zitnik, 2005; Schiff et al., 2006). Nonetheless, pooled analyses of data from the RA clinical testing programs of etanercept and adalimumab have yielded evidence suggesting that anti-TNF-alpha therapy does not confer an increased overall risk of serious infection. In those analyses, rates of serious infection among patients receiving etanercept (3-6 per 100 patient years) and patients receiving adalimumab (5.1 per 100 patient-years) were comparable to previously reported background rates of serious infection in RA populations (Doran, Crowson, Pond, O’Fallon, & Gabriel, 2002; Lebwohl et al., 2005; Schiff et al., 2006; Singh, Ramey, Rausch, & Schettler, 1999).

Also noteworthy with regard to serious adverse events is that analyses of safety data from the RA clinical testing programs for each of the three available TNF-alpha antagonists have revealed that rates of lymphoma incidence among patients receiving TNF-alpha antagonist therapy in RA clinical trials are (after adjustment for age and gender) 2 to 6 times higher than the rate of lymphoma incidence in the general population (FDA Arthritis Advisory Committee, 2003; Schiff et al., 2006). Nonetheless, despite these findings, it is unclear whether there is a true causal link between TNF-alpha blockade and lymphoma. Clouding the issue are data indicating that independent of TNF-alpha antagonist use, patients with RA, and particularly those with more severe RA (who are over- represented in clinical trial populations), have an elevated lymphoma risk relative to the general population. For instance, epidemiologic studies indicate that the background incidence of lymphoma among patients with RA is (after adjustment for age and gender) 2.0 to 2.7 times higher than the general incidence of lymphoma (Gridley et al., 1993; Isomaki, Hakulinen, & Joutsenlahti, 1978). Meanwhile, a case-control study involving a population-based Swedish RA cohort found that after controlling for treatment, the odds of developing lymphoma are 5.4 and 25.8 times higher, respectively, for patients with moderately and highly active RA than for patients with low levels of RA activity (Baecklund, Ekbom, Sparen, Feltelius, & Klareskog, 1998). In clinical testing, the incidence of lymphoma in patients with RA who received anti-TNF- alpha therapy was higher than the incidence that would be expected in a comparable cohort sampled from the general population, and as a result, there is speculation that anti-TNF-alpha therapy may confer an increased risk of lymphoma. However, because patients with RA, and particularly more severe RA, appear to have an inherently increased risk of lymphoma, it is difficult to say whether such speculation is accurate or whether the increased lymphoma incidence seen in patients with RA relative to the general population during clinical testing of anti-TNF-alpha therapy simply reflects the fact that patients with severe RA inherently have a strong predisposition to develop lymphoma, regardless of what treatment they receive.

Other serious adverse events to which TNF-alpha antagonist use has been linked include congestive heart failure (CHF) and demyelination. Specifically, clinical trials of TNF-alpha antagonist therapy for multiple sclerosis (MS) and for moderate-to-severe CHF have shown, paradoxically, that TNF-alpha blockade may be associated to some extent with the worsening of existing cases of MS and moderate-to-severe CHF (Chung, Packer, Lo, Fasanmade, & Willerson, 2003; Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, 1999). Cases of demyelination and CHF exacerbation in patients given TNF-alpha antagonists have also been reported outside the clinical trial setting (Kwon, Cote, Cuffe, Kramer, & Braun, 2003; Mohan et al., 2001). Anecdotal reports have linked TNF-alpha antagonist therapy to additional rare but serious adverse events, including lupus-like syndromes, severe administration-site reactions, and severe hematologic toxicity (Furst et al., 2006). Furthermore, cases of severe liver injury occurring in association with infliximab use have been reported (Garcia Aparicio, Rey, Sanz, & Alvarez, 2006; Tobon, Canas, Jaller, Restrepo, & Anaya, 2007).

Pretreatment screening of candidates for TNF-alpha antagonist therapy represents a key step toward minimizing the incidence of serious treatment-related adverse events. In particular, findings made at pretreatment screening – including historical findings, laboratory findings, and physical examination findings – enable the treating clinician to make an informed decision on whether the candidate being screened can be treated safely with a TNF-alpha antagonist. Also critical for the optimization of TNF-alpha antagonist safety are pretreatment measures specifically addressing the issue of TB risk. Current guidelines for minimizing TB risk state that every patient preparing to begin anti-TNF-alpha therapy should undergo tuberculin skin testing (TST) to determine whether he or she is carrying an MTB infection. Those same guidelines also state that in the absence of other concerns, TST-negative patients may begin TNF-alpha antagonist therapy immediately. However, for TST- positive patients, it is recommended that chest x-ray (CXR) be performed to determine whether the MTB infection detected on TST is latent or active. It is further recommended that, as a prerequisite for the initiation of TNF-alpha antagonist therapy, patients found to have latent infection on CXR begin preventive anti-TB therapy, whereas those showing active infection have their TB treated to resolution (Hochberg et al., 2005). A patient who has latent TB can begin with anti-TNF-alpha therapy once he or she has begun TB prophylaxis, while a patient who has active TB can begin anti-TNF- alpha therapy once his or her active TB has been treated to resolution.

Once TNF-alpha antagonist therapy has been initiated for a given patient, the treating clinician can continue to work toward ensuring the safety of that patient by conducting follow-up evaluation on a regular basis (typically every 2-3 months) and by adjusting the patient’s treatment regimen as needed based on the findings made at follow-up. With regard to possible adjustments, the temporary cessation of treatment may be warranted if follow-up reveals that the patient being evaluated will be entering into a shortterm scenario in which he or she may have an abnormally elevated risk of experiencing a serious treatment-related adverse event. As an example, in Carl’s case, anti-TNF-alpha therapy was halted for a period before and immediately after immunization, so as to minimize the likelihood of opportunistic infection by the pathogens to which Carl would be exposed through immunization with live vaccines. It is generally the practitioner’s discretion to determine how long before vaccination anti-TNF-alpha therapy is stopped and how long after vaccination anti-TNF-alpha therapy is restarted.

Carl’s case raises an additional important point regarding the steps that clinicians can take to ensure that TNF-alpha antagonist therapy is used to optimal benefit. Specifically, the case in question demonstrates that for a patient who experiences treatment failure while taking a particular TNF-a antagonist, switching to a different anti-TNF-alpha agent may prove beneficial. The potential value of switching TNF-alpha antagonists is documented most clearly in the RA literature (Nikas et al., 2006; van Vollenhoven, 2004). In fact, in one small, controlled trial, patients with RA who had recently discontinued infliximab (for efficacy, safety, or tolerability related reasons) and patients with RA who were TNF- alpha antagonist-naive at baseline were both assigned to treatment with adalimumab. It was found that at the end of the 12-month trial period, rates of clinical response in the former group and in the latter group were nearly identical (Nikas et al., 2006). Nonetheless, there is anecdotal evidence to support the idea that switching TNF-alpha antagonists can produce favorable results in the setting of psoriatic disease as well (Delaunay et al., 2005; Smith, Gadsby, & Deighton, 2007).

Clearly, evidence in RA is not directly translatable to the setting of psoriasis, but both RA and psoriasis are inflammatory, immune-mediated diseases in which TNF plays a role. Therefore, in the absence of more complete data from the setting of psoriasis, it seems worthwhile to note the RA data that are available.

Summary

Clinicians can play an important role in ensuring the optimal use of TNF-alpha antagonist therapy. With regard to the optimization of safety, patients receiving TNF-alpha antagonist therapy may, in rare cases, experience serious adverse events in association with treatment; however, by taking appropriate steps in the pretreatment period and after TNF-alpha antagonist therapy is underway, clinicians can help minimize the likelihood of serious treatment- related adverse events and limit the harmful impact of such events when they do occur. Safety considerations notwithstanding, intervention on the part of the clinician may also be valuable for maximizing the overall utility of TNF-alpha antagonist therapy. One intervention that may be particularly relevant in this regard is the switching of TNF-alpha antagonists, as switching may permit patients to experience the benefits of TNF-alpha antagonist therapy even after treatment with an index TNF-alpha antagonist has failed.

Conclusions

Psoriasis and PsA are conditions that can have serious untoward effects on patient well-being. Therefore, it is vitally important that both conditions be treated in an effective manner. To that end, it is desirable for clinicians to adopt a case-by-case approach to the management of psoriatic disease, as the most appropriate management strategy for a given patient will depend on that patient’s distinctive clinical and psychosocial features, as well as on his or her unique expectations with regard to therapeutic outcomes. Still, while the value of taking a case-by-case approach is clear, there are broadly applicable principles that may provide guidance as it relates to the management of affected patients. The cases presented in this Supplement highlight certain of those principles; specifically, that the optimization of outcomes in PsA is contingent upon early detection of the disease and prompt treatment with a disease-modifying agent; that many patients who receive traditional systemic therapy may benefit from switching to TNF-alpha antagonist therapy; and that active involvement on the part of the treating clinician is necessary for ensuring that TNF- alpha antagonist therapy is employed to optimal benefit. By taking these points into consideration, clinicians may be better able to develop and execute individualized management strategies that maximize the likelihood of favorable clinical, psychological, and functional outcomes for patients with psoriatic disease. This article and the CNE answer/evaluation form are also available online at www.dermatologynursing.net

Free CNE for this and another Supplement on psoriatic disease are available at www.dermatologynursing.net

Objectives

This continuing nursing education (CNE) activity is designed for nurses and other health care providers who care for and educate patients and their families regarding psoriatic disease. For those wishing to obtain CNE credit, an evaluation follows. After studying the information presented in this article, the nurse will be able to:

1. Describe the basic characteristics of psoriatic disease.

2. Discuss the need for early and aggressive intervention of psoriatic disease.

3. Explain the transition from traditional to biologic therapy for psoriatic disease.

4. Recognize ways to optimize treatment outcomes for patients with psoriasis.

Given the untoward consequences associated with psoriatic disease, it is critical that psoriasis and PsA be managed appropriately.

It is not uncommon for PsA to be accompanied by chronic fatigue, which in some cases may be quite severe.

Of late, changes in the psoriatic disease treatment paradigm have expanded opportunities for the use of systemic therapies in general.

Pretreatment screening of candidates for TNF-alpha antagonist therapy represents a key step toward minimizing the incidence of serious treatment-related adverse events.

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Mary Wiatrowski, RN, DNC, is Clinical Coordinator, Texas Dermatology Associates’ Specialty Psoriasis Clinic, Dallas, TX.

Nicole Furfaro, MSN, ARNP, is a Nurse Practitioner, Seattle Rheumatology Associates, Seattle, WA.

Copyright Anthony J. Jannetti, Inc. Oct 2007

(c) 2007 Dermatology Nursing. Provided by ProQuest Information and Learning. All rights Reserved.