Psoriatic Arthritis: Current Therapy and Future Approaches
Psoriatic Arthritis: Current Therapy and Future Approaches
NSAIDs and corticosteroids are often prescribed as part of the management of inflammatory joint diseases, including PsA. While concerns had been raised about their safety, a recent Cochrane review evaluating the safety of NSAIDs and paracetamol in inflammatory arthritides suggested that overall NSAIDs may be used safely with MTX without an increased risk of toxic adverse events or liver, renal or pulmonary dysfunction. Also, a placebo-controlled study of nimesulide, a selective cyclooxygenase 2 (COX-2) inhibitor, did result in improved signs and symptoms of PsA and, contrary to prior suggestions, NSAID use did not worsen skin disease.
Systemic and IA steroids are commonly used for PsA, although again there are limited data confirming their utility specifically in PsA. Nevertheless, it should be noted that between 40% and 50% of patients in clinical trials are or have previously been on oral steroids. One small study compared the use of early IA steroid injection vs conservative management with NSAIDs in early PsA patients presenting with oligoarticular disease. In this study, patients also received SSZ if synovitis persisted or if polyarticular disease occurred. By week 52, 81% of patients on the IA steroid achieved complete response, defined by the absence of synovitis, compared with only 51% in the conservative group. It should be noted that SSZ was started in a greater percentage of the steroid group (45%) as compared with the conservative group (14%) and the study contained a mixture of patients with oligoarticular arthritis, of whom few had an established diagnosis of PsA.
Among DMARDs, SSZ has one of the larger bodies of evidence specifically in PsA. In a placebo-controlled trial of 221 PsA patients there was improvement in peripheral arthritis in 59% of SSZ-treated patients compared with 47% of controls; however, the overall effect size was small. Similarly a smaller double-blind randomized controlled trial (RCT) suggested that the use of SSZ provided improvement in functional outcomes and to a lesser degree skin disease. Unfortunately there is no documented benefit of SSZ with regard to inhibition of joint damage as assessed by radiographic progression.
LEF, an inhibitor of pyrimidine synthesis, was studied in a multinational double-blind RCT called the Treatment of PsA Study (TOPAS). Overall, 58.9% of the LEF-treated patients were clinical responders, compared with 29.7% of placebo controls. LEF was superior to placebo in functional status scores, CRP reduction and 75% improvement in the PASI75. In a small retrospective study of patients who were considered non-responders to MTX, patients who received a combination of LEF and MTX had improvements in their 28-joint DAS (DAS28) and EULAR response criteria compared with those receiving MTX monotherapy. The combination of MTX and LEF can be associated with elevated liver function tests and requires careful monitoring.
CSA and tacrolimus inhibit calcineurin, resulting in the inhibition of T lymphocyte activation. CSA has been shown to be effective in improving both skin and joint involvement in a number of clinical studies in psoriasis and PsA. CSA has also been shown to be effective in combination with MTX and TNF inhibitor (TNFi). A double-blind RCT that compared combination CSA + MTX with MTX or placebo in PsA showed significant improvement in CRP, PASI, swollen joint count and US-defined synovitis with combination CSA + MTX. Combinations of CSA with TNFi have also shown positive results in an open label prospective study of 160 patients receiving monotherapy CSA, monotherapy adalimumab (ADA) or combination CSA + ADA. PsA patients on combination CSA + ADA had statistically significant improvements in Psoriatic Arthritis Response Criteria (PsARC), ACR50 and HAQ assessments at 12 months compared with those on monotherapy, although there was little difference in PASI outcomes between the groups. The popularity of CSA use has been tempered by the need for close monitoring due to concerns about renal toxicity and hypertension, especially at doses >3 mg/kg/day.
MTX is widely accepted as a cornerstone therapy in PsA, as reflected in both the GRAPPA and EULAR treatment recommendations. Despite its popularity there is a paucity of studies assessing MTX use in PsA, and results have been disparate. The MTX in PsA trial randomized 221 PsA patients to placebo or 15 mg of MTX weekly for 6 months. The overall results suggested significant efficacy for MTX only in the physician global assessment and PASI, and the primary outcomes were not achieved. However, a number of factors in study design may have contributed to these results, including a high dropout rate, a relatively low dose of MTX and inclusion of PsA patients with less severe disease. Indeed, when analysis was restricted to polyarticular patients, MTX was effective.
A recent systematic analysis reviewed the five RCTs in the medical literature and about a dozen other observational studies. Although disparate results were reported in the individual studies, in general it appeared that trials using weekly doses of MTX of ≥15 mg achieved clinical benefit, whereas those using smaller doses did not. Further support for the efficacy of MTX comes from the open-label RESPOND study, in which 115 treatment-naive PsA patients were randomized to receive combination MTX + infliximab or MTX monotherapy at a dose of 15 mg. At 16 weeks, 86% of patients received an ACR20 response rate with combination therapy, as did 66% of patients on MTX monotherapy. Overall, despite the paucity of evidence, MTX remains a mainstay of drug therapy in PsA.
The introduction of biologic therapies with anti-TNFis has greatly improved the clinician's ability to treat all of the various manifestations of PsA. The clinical efficacy of TNFis exceeds that of traditional DMARDs and TNFis have been shown to significantly inhibit joint damage as assessed by radiographic progression. Currently five TNFis are approved by the US Food and Drug Administration (FDA) for use in PsA: infliximab, etanercept, ADA, golimumab and, most recently, certolizumab pegol (Table 1). Overall, efficacy among the agents appears comparable, although there have not been head-to-head trials. An indirect comparison reviewing data from RCTs of the first four approved TNFis, and focusing on changes in skin, peripheral joint and axial involvement, suggested that there were no significant differences between the TNFis in PsA. Studies of certolizumab pegol, the most recently approved agent, included patients who had previously been treated with other TNFis, and showed efficacy comparable to TNFi-naive patients. This suggests that TNFi switching may be viable in PsA, as has been established in RA. Data supporting this concept also come from registries. In the Norwegian DMARD (NOR-DMARD) registry, the durability of remaining on a second TNFi was less than that for the first TNFi course, but suggested that some patients will respond to TNFi switching. Similarly in DANBIO (a nationwide registry of biologic therapies in Denmark), retention rates on a second or even a third TNFi suggest that switching TNFis can result in clinical improvement.
Factors such as cost and patients' concerns regarding side effects over the long term have raised the question of whether treatments might be tapered or even withdrawn in patients achieving low levels of disease activity. In RA, studies have suggested that such a strategy might be viable for a subset of patients, particularly those with earlier disease who achieve very low levels of disease activity on treatment. In PsA, to date there has been only one prospective case–control study addressing this. Dose reduction of ADA to 40 mg every 4 weeks was done in a population that included 76 PsA patients who had obtained clinical remission. At the 28-week follow-up, 88.6% of PsA patients remained in clinical remission; interestingly, only 17.6% of the RA patients in the study remained in remission. Other studies addressing dose reduction and withdrawal are currently under way and may help define the patient characteristics that predict success on lower doses of specific agents.
Common Conventional Treatment Agents
NSAIDs and corticosteroids
NSAIDs and corticosteroids are often prescribed as part of the management of inflammatory joint diseases, including PsA. While concerns had been raised about their safety, a recent Cochrane review evaluating the safety of NSAIDs and paracetamol in inflammatory arthritides suggested that overall NSAIDs may be used safely with MTX without an increased risk of toxic adverse events or liver, renal or pulmonary dysfunction. Also, a placebo-controlled study of nimesulide, a selective cyclooxygenase 2 (COX-2) inhibitor, did result in improved signs and symptoms of PsA and, contrary to prior suggestions, NSAID use did not worsen skin disease.
Systemic and IA steroids are commonly used for PsA, although again there are limited data confirming their utility specifically in PsA. Nevertheless, it should be noted that between 40% and 50% of patients in clinical trials are or have previously been on oral steroids. One small study compared the use of early IA steroid injection vs conservative management with NSAIDs in early PsA patients presenting with oligoarticular disease. In this study, patients also received SSZ if synovitis persisted or if polyarticular disease occurred. By week 52, 81% of patients on the IA steroid achieved complete response, defined by the absence of synovitis, compared with only 51% in the conservative group. It should be noted that SSZ was started in a greater percentage of the steroid group (45%) as compared with the conservative group (14%) and the study contained a mixture of patients with oligoarticular arthritis, of whom few had an established diagnosis of PsA.
SSZ
Among DMARDs, SSZ has one of the larger bodies of evidence specifically in PsA. In a placebo-controlled trial of 221 PsA patients there was improvement in peripheral arthritis in 59% of SSZ-treated patients compared with 47% of controls; however, the overall effect size was small. Similarly a smaller double-blind randomized controlled trial (RCT) suggested that the use of SSZ provided improvement in functional outcomes and to a lesser degree skin disease. Unfortunately there is no documented benefit of SSZ with regard to inhibition of joint damage as assessed by radiographic progression.
LEF
LEF, an inhibitor of pyrimidine synthesis, was studied in a multinational double-blind RCT called the Treatment of PsA Study (TOPAS). Overall, 58.9% of the LEF-treated patients were clinical responders, compared with 29.7% of placebo controls. LEF was superior to placebo in functional status scores, CRP reduction and 75% improvement in the PASI75. In a small retrospective study of patients who were considered non-responders to MTX, patients who received a combination of LEF and MTX had improvements in their 28-joint DAS (DAS28) and EULAR response criteria compared with those receiving MTX monotherapy. The combination of MTX and LEF can be associated with elevated liver function tests and requires careful monitoring.
CSA and Tacrolimus
CSA and tacrolimus inhibit calcineurin, resulting in the inhibition of T lymphocyte activation. CSA has been shown to be effective in improving both skin and joint involvement in a number of clinical studies in psoriasis and PsA. CSA has also been shown to be effective in combination with MTX and TNF inhibitor (TNFi). A double-blind RCT that compared combination CSA + MTX with MTX or placebo in PsA showed significant improvement in CRP, PASI, swollen joint count and US-defined synovitis with combination CSA + MTX. Combinations of CSA with TNFi have also shown positive results in an open label prospective study of 160 patients receiving monotherapy CSA, monotherapy adalimumab (ADA) or combination CSA + ADA. PsA patients on combination CSA + ADA had statistically significant improvements in Psoriatic Arthritis Response Criteria (PsARC), ACR50 and HAQ assessments at 12 months compared with those on monotherapy, although there was little difference in PASI outcomes between the groups. The popularity of CSA use has been tempered by the need for close monitoring due to concerns about renal toxicity and hypertension, especially at doses >3 mg/kg/day.
MTX
MTX is widely accepted as a cornerstone therapy in PsA, as reflected in both the GRAPPA and EULAR treatment recommendations. Despite its popularity there is a paucity of studies assessing MTX use in PsA, and results have been disparate. The MTX in PsA trial randomized 221 PsA patients to placebo or 15 mg of MTX weekly for 6 months. The overall results suggested significant efficacy for MTX only in the physician global assessment and PASI, and the primary outcomes were not achieved. However, a number of factors in study design may have contributed to these results, including a high dropout rate, a relatively low dose of MTX and inclusion of PsA patients with less severe disease. Indeed, when analysis was restricted to polyarticular patients, MTX was effective.
A recent systematic analysis reviewed the five RCTs in the medical literature and about a dozen other observational studies. Although disparate results were reported in the individual studies, in general it appeared that trials using weekly doses of MTX of ≥15 mg achieved clinical benefit, whereas those using smaller doses did not. Further support for the efficacy of MTX comes from the open-label RESPOND study, in which 115 treatment-naive PsA patients were randomized to receive combination MTX + infliximab or MTX monotherapy at a dose of 15 mg. At 16 weeks, 86% of patients received an ACR20 response rate with combination therapy, as did 66% of patients on MTX monotherapy. Overall, despite the paucity of evidence, MTX remains a mainstay of drug therapy in PsA.
TNF Inhibitors
The introduction of biologic therapies with anti-TNFis has greatly improved the clinician's ability to treat all of the various manifestations of PsA. The clinical efficacy of TNFis exceeds that of traditional DMARDs and TNFis have been shown to significantly inhibit joint damage as assessed by radiographic progression. Currently five TNFis are approved by the US Food and Drug Administration (FDA) for use in PsA: infliximab, etanercept, ADA, golimumab and, most recently, certolizumab pegol (Table 1). Overall, efficacy among the agents appears comparable, although there have not been head-to-head trials. An indirect comparison reviewing data from RCTs of the first four approved TNFis, and focusing on changes in skin, peripheral joint and axial involvement, suggested that there were no significant differences between the TNFis in PsA. Studies of certolizumab pegol, the most recently approved agent, included patients who had previously been treated with other TNFis, and showed efficacy comparable to TNFi-naive patients. This suggests that TNFi switching may be viable in PsA, as has been established in RA. Data supporting this concept also come from registries. In the Norwegian DMARD (NOR-DMARD) registry, the durability of remaining on a second TNFi was less than that for the first TNFi course, but suggested that some patients will respond to TNFi switching. Similarly in DANBIO (a nationwide registry of biologic therapies in Denmark), retention rates on a second or even a third TNFi suggest that switching TNFis can result in clinical improvement.
Factors such as cost and patients' concerns regarding side effects over the long term have raised the question of whether treatments might be tapered or even withdrawn in patients achieving low levels of disease activity. In RA, studies have suggested that such a strategy might be viable for a subset of patients, particularly those with earlier disease who achieve very low levels of disease activity on treatment. In PsA, to date there has been only one prospective case–control study addressing this. Dose reduction of ADA to 40 mg every 4 weeks was done in a population that included 76 PsA patients who had obtained clinical remission. At the 28-week follow-up, 88.6% of PsA patients remained in clinical remission; interestingly, only 17.6% of the RA patients in the study remained in remission. Other studies addressing dose reduction and withdrawal are currently under way and may help define the patient characteristics that predict success on lower doses of specific agents.
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