Current and investigational treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is now recognised as a progressively destructive inflammatory arthritis that can lead to joint deformity and functional disability. Early diagnosis and treatment with disease-modifying antirheumatic drugs (DMARDs) are necessary to control disease, particularly in patients with clinical factors and human leukocyte antigen markers predictive of progressive disease. However, there are few randomised controlled trials of the traditional DMARDs in PsA and none have demonstrated efficacy on axial manifestations or delay in radiological progression. The demonstration of raised levels of TNF-alpha in psoriatic skin and synovial tissue has provided a rationale for the application of biological agents in PsA. Furthermore, the recognition of the role of T-cell activation in both psoriasis and PsA has led to the therapeutic targeting of T lymphocytes, the results of which at this early stage are encouraging. This article reviews the studies of the most widely used traditional DMARDs in PsA followed by studies with leflunomide and the biological response modifiers, including TNF-alpha antagonists and T-cell-targeted therapies.     

Economic burden of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic autoimmune disease characterized by inflammatory arthritis in association with skin psoriasis (Ps). PsA may show a heterogeneous and variable clinical course, with involvement of peripheral and axial diarthrodial joints, periarticular structures such as entheses, as well as the skin and nails. Evidence is increasing that affected patients can have significant radiographic joint damage, functional impairment, reduced quality of life (QOL) and long-term work disability. The economic burden of PsA can be considerable.There is an increasing interest in pharmacoeconomic evaluations in PsA, driven mostly by the introduction of highly effective but expensive biologic agents, particularly inhibitors of the proinflammatory cytokine tumour necrosis factor (TNF)-alpha. Treatment with TNFalpha inhibitors results in not only substantial improvements in signs and symptoms of arthritis, but also improvements in all distinct sites of the disease, such as axial arthritis, dactylitis, enthesitis and skin disease.There is a dearth of published pharmacoeconomic evaluations in the field of PsA. The notable clinical efficacy of the TNFalpha inhibitors needs to be factored into a comprehensive assessment of their value. Further analyses are needed to optimize the use of the new biologic agents in PsA.     

Traditional and newer therapeutic options for psoriatic arthritis: an evidence-based review

Psoriatic arthritis (PsA) is a destructive form of inflammatory arthritis that occurs in about one-third of patients with psoriasis. The pathogenesis of PsA includes genetic and immunological factors. A review of the currently available therapies reveals that traditional disease-modifying medications have provided only marginal relief from joint inflammation in patients with PsA, and have not been successful in controlling the disease and preventing joint damage. On the basis of current understanding of the pathogenesis of joint destruction in PsA, several new medications have been introduced, including anti-tumour necrosis factor (TNF) agents and agents that interfere with T-cell function. Most of these medications have been found to be effective in both psoriasis and PsA. Recent randomised controlled trials suggest that at least anti-TNF agents may help prevent progression of joint destruction.     

Diagnosis and management of psoriatic arthritis

Psoriatic arthritis (PsA) is considered to be one of the spondyloarthritides, and as such has both spinal and peripheral joint involvement. In 80% of patients, psoriasis usually precedes the development of arthritis. Although there are no widely accepted diagnostic criteria, a number of distinct clinical features allow it to be distinguished from other forms of inflammatory arthritis. It affects both sexes equally, and the pattern of joint involvement is characteristic with distal interphalangeal joint involvement, asymmetry, dactylitis, flail or ankylotic deformities of digits, and the frequent presence of enthesitis and spinal involvement. It may have a pattern of joint involvement similar to rheumatoid arthritis (RA) but in these patients rheumatoid factor and the other systemic features of RA are usually absent. Radiographs frequently reveal evidence of asymmetric sacroiliitis and spinal disease, and peripheral joints, as well as showing erosions, may also demonstrate profuse new bone formation and ankylosis. Profound osteolysis producing the pencil-in-cup deformity can also occur in the same individual. It is now recognised that PsA can be a destructive arthritis with an increased morbidity and mortality. Studies of standard disease-modifying therapies have been small and frequently inconclusive because of a high placebo response rate. This may be as a result of heterogeneity in patient selection, poor assessment tools, or the difference in underlying pathogenesis and subsequent response to therapy. In meta-analyses, sulfasalazine and methotrexate have been shown to be effective. Treating the skin alone seems to have little impact on joint disease, and the relationship between skin and joints is still unclear. However, recent studies with anti-tumour necrosis factor agents, such as etanercept and infliximab, have shown considerable significant clinical benefit and provided the hope that we will at last have effective therapies for this disease.     

改变病情抗风湿药治疗银屑病关节炎的回顾性临床研究

目的分析改变病情抗风湿药(DMARDs)治疗银屑病关节炎(PsA)的用药状况、疗效及安全性。方法对114例住院PsA患者使用DMARDs的情况进行总结,并分析其中66例随访资料完整者的疗效和安全性。结果109例(95.6%)使用DMARDs,61例(53.5%)使用非甾体抗炎药(NSAIDs)、33例(28.9%)使用糖皮质激素,7例(6.1%)使用植物药,3例(2.6%)使用生物制剂。94例(82.5%)患者使用甲氨蝶呤(MTX),其次为柳氮磺吡啶(SSZ)64例(56.1%)、来氟米特(LEF)27例(23.7%);治疗方案包括联合用药82例(75.2%),单一用药27例(24.8%)。随访的66例患者中,对皮肤和关节同时有效者24例(36.4%),其中13例复发。常用治疗方案中,MTX联合LEF和/或SSZ的疗效显著优于LEF,不良反应没有增加。结论DMARDs是治疗PsA的最常用药,其中MTX使用最多,治疗方案以联合用药为主,但总体疗效并不高。PsA的治疗应选择MTX、LEF和/或SSZ的联合方案。     

The psoriatic patient profile for infliximab

Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the population worldwide. Psoriasis results from a complex and dynamic interplay between genetic and environmental factors that trigger an excessive inflammatory response in the skin which is driven by several mediators including TNF-alpha. The common form of the disease, termed 'chronic plaque psoriasis' is characterized by erythematous scaly plaques, typically on elbows, knees, scalp and buttocks. Psoriasis does not only affect the skin but also the nails and sometimes it is associated to a form of negative spondyloarthropathy, named the psoriatic arthritis (PsA), which could affect joints, tendons and/or the bone. Moreover, psoriasis is also frequently associated to metabolic comorbidities including obesity, dyslipidemia, diabetes and non alcoholic fatty liver disease. Consequently, psoriasis causes a high degree of morbidity and impairment of quality of life. There is no definite cure for psoriasis although there are treatments which could induce its remission. During the past decade, new very selective biological therapies for the management of psoriasis have been licensed. Biological drugs include TNF-alpha inhibitors (etanercept, infliximab and adalimumab) and ustekinumab which is an anti-IL 2/23 monoclonal antibody. Infliximab is very effective in the treatment of psoriasis either with nail involvement and/or PsA. Considering the characteristics of this drug, we propose a specific profile of the patient candidate to infliximab treatment. In particular, the main patient characteristics which drive the physician in selecting infliximab include the presence of a severe chronic plaque psoriasis, particularly if it is associated to a severe nail involvement and/or PsA, the urgency of psoriasis clearing, poor compliance of the patient for self-medication and the prospective of a long term continuous treatment.     

Current concepts in clinical therapeutics: disease-modifying drugs for rheumatoid arthritis

The epidemiology, pathophysiology, clinical features, diagnosis, and clinical course of rheumatoid arthritis (RA) and the role of disease-modifying antirheumatic drugs (DMARDs) in its treatment are reviewed. RA, a widespread disease affecting people of all races and sexes around the world, has an unknown and perhaps multifactorial etiology. Conflicting evidence supports an immune-complex, infectious, metabolic, or genetic basis for RA. The disease affects diarthrodial joints and begins as an immune response to unknown antigenic stimuli. A proliferative process ensues, leading to formation of a vascular lesion called a pannus, which then infiltrates into cartilage, subchrondral bone, and tendon. This destructive phase leads to classic RA symptoms of pain, limitation of motion, swelling, heat, and redness of the affected joint. Symptoms and laboratory tests form the basis for diagnosis. For most RA patients, conservative therapy provides substantial benefit. In those patients who suffer from unrelenting and progressively destructive disease, more aggressive intervention is necessary to prevent permanent disability. The DMARDs are reserved for treatment of this group of patients. DMARDs include such diverse agents as the gold compounds aurothioglucose, auranofin, and gold sodium thiomalate; the antimalarials hydroxychloroquine sulfate and chloroquine phosphate; penicillamine; and the cytotoxic agents azathioprine, methotrexate, and cyclophosphamide. DMARDs are effective but toxic therapeutic agents. Because of the toxicities of these agents, careful monitoring at regular intervals is necessary throughout the duration of therapy. For patients in whom these drugs demonstrate efficacy and are tolerated, the DMARDs may attenuate the disabling effects of long-term erosive disease.     

Psoriatic arthritis: genetic susceptibility and pharmacogenetics

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. The etiology of PsA is unknown; however, there is mounting evidence for a strong genetic contribution to PsA. A few disease-related genes have already been identified in PsA. Cytokines associated with PsA appear to be the most promising targets for pharmacogenetics. Blockade of TNF-alpha and IL-12/23 is associated with a marked clinical response to PsA and/or psoriasis, implying a pivotal role of these cytokines in the pathogenesis of these two disease entities. To date, only the -308 variant of the TNF-alpha promoter gene has been shown to be important in predicting response to TNF-alpha blockade in inflammatory arthritis.     

An evaluation of tofacitinib for the treatment of psoriatic arthritis

ABSTRACT

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory condition that is associated with progressive joint destruction and reduced quality of life. Despite the common use of disease-modifying anti-rheumatic drugs (DMARDs) in PsA, their influence has been investigated in a number of studies with conflicting results. There is also concern about their safety and tolerability. Tofacitinib is an orally administered Janus kinase (JAK) inhibitor that has recently been approved for the treatment of PsA by various international regulatory authorities, including the FDA, EMA, and NICE.

Areas covered: In this review, the mechanism of action and the pharmacokinetic properties of tofacitinib are discussed. The data from two large phase III clinical studies evaluating the use of tofacitinib in PsA is also discussed in addition to the findings from other relevant studies.

Expert opinion: The clinical data demonstrate significant improvement in disease activity in PsA patients using tofacitinib. There is also an acceptable clinical safety profile for the drug. Tofacitinib has various advantages over several existing drug treatments for PsA including an oral route of administration, a short half-life and a fast onset of action. Consequently, we anticipate that tofacitinib will become an increasingly used targeted synthetic DMARD (tsDMARD) for active PsA over the coming years.     

Immunopathogenesis of psoriatic arthritis: Recent advances

Psoriatic Arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. The pathophysiology of PsA includes genetic, environmental and immunologic factors. Recent studies revealed the dynamic role of the immune system in the pathogenesis of the disease. Adhesion molecules, proinflammatory cytokines, angiogenic factors and metalloproteinases appear to orchestrate the inflammatory response in PsA. This article summarizes the current immunologic findings and suggests future therapeutic and researching approaches in the field of PsA.     

Anti-TNF agents for the treatment of spondyloarthropathies

For the treatment of spondyloarthropathies (SpA), therapeutic options using disease-modifying drugs are rather limited compared to other inflammatory rheumatic diseases such as rheumatoid arthritis (RA). This is especially true for the spinal symptoms of the spondyloarthropathies, of which ankylosing spondylitis (AS) is the prototype. New TNF-alpha blockers have been proven highly effective in improving the spinal symptoms and extra-spinal manifestations of SpA. Convincing data in the form of placebo-controlled trials are already available for AS and psoriatic arthritis (PsA). However, limited data suggests that TNF-alpha blockers might be similarly effective in other spondylolarthropathies. Side effects, mainly infections and allergic reactions, occur similar to those observed in RA treatment. Currently, there is no reason to combine TNF-alpha blockers with other disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of AS and other SpA, as these DMARDs are not effective. Thus, TNF-alpha blockers seem to be a major breakthrough in the treatment of SpA. The patients who are primary candidates for such treatments are yet to be defined, particularly in light of the high costs and unknown long-term side effects involved. Furthermore, future studies need to show whether these biologicals not only suppress inflammation but also prevent long-term bony damage.     

TNF inhibitors for inflammatory arthritis in New Zealand

For the vast majority of the estimated 100,000 New Zealanders who suffer from rheumatoid arthritis (RA), relatively inexpensive disease-modifying antirheumatic drugs (DMARD) regimens are sufficient to control inflammatory disease and maintain long-term function. Some DMARDs have been shown to slow, but not arrest, the progression of erosions. All but a few of those who suffer from ankylosing spondylitis (AS) can manage full social participation with non-steroidal anti-inflammatory drugs (NSAIDs) and an exercise regimen. For the small subset of arthritis sufferers who have disabling pain and progressive damage from uncontrolled inflammatory disease, the advent of the biological era offered great promise. In most of the developed world, this promise is being delivered to patients with an expanding range of diseases including RA, AS, and psoriatic arthritis, but central government (PHARMAC) funding for TNF inhibitors in New Zealand has until recently been limited to etanercept for approximately 40 patients with juvenile inflammatory arthritis.     

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白联合甲氨蝶呤治疗银屑病关节炎的临床疗效和安全性初步研究

目的评价重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(rhTNFR:Fc;商品名:益塞普)联合甲氨蝶呤治疗银屑病关节炎(PsA)患者的临床疗效以及安全性。方法本研究为对照开放性试验,共纳入16例活动期脊柱病型PsA患者,至少服用甲氨蝶呤10～15mg/周联合非甾体抗炎药3个月临床未缓解。试验组加用rhTNFR:Fc每周50mg皮下注射,对照组加用其他改善病情抗风湿药(DMARDs)(来氟米特3例,沙利度胺3例,柳氮磺吡啶2例)。主要评价指标为2,4,8,12周达到强直性脊柱炎(AS)评价标准(ASAS)20改善的比例以及银屑病皮损面积和严重性指数(PSI75),次要评价指标包括上述时间达到ASAS50改善的比例以及PSI50,ASAS评分系统各单项指标的变化。并同时记录2组药物不良反应。计量资料比较采用t检验或Wilcoxon秩和检验,计数资料比较采用χ2检验。结果第2周对照组所有指标较基线均无明显改善,而试验组均明显改善(P<0.05)。至12周时试验组及对照组达到ASAS20改善的患者数分别为7例(7/8)及2例(2/8),2组比较差异有统计学意义(P<0.05)。试验组ASAS50、PSI75、PSI50均明显优于对照组。2组均未见严重不良反应发生。结论 rhTNFR:Fc治疗PsA能明显改善脊柱关节症状,减轻皮损,并且具有良好的安全性和耐受性。     

Treatment strategies for early psoriatic arthritis

Background: Until a few years ago, the early diagnosis of psoriatic arthritis (PsA) did not receive much attention, especially in view of the lack of drugs capable of altering the disease course. This changed with the introduction of the TNF-α-blocking agents, as a result of which the early diagnosis of PsA is now a topic of great interest. Objective: The aim of the study was to review the treatment for PsA in order to determine the optimal approach to managing early disease. Methods: The systematic review performed by members of GRAPPA (Group of Research and Assessment of Psoriasis and Psoriatic Arthritis) was integrated with data from more recent studies. Results/conclusion: After making the diagnosis of PsA, the next step is to stage of the disease with the aim of establishing the prevalent manifestation (peripheral arthritis, peripheral enthesitis, axial involvement and dactylitis) and degree of severity (mild, moderate or severe) of the disease. Each patient should be treated according to the defined disease status following the suggested treatment algorithms.     

Update on Treatment of Rheumatoid Arthritis

Objective:To review current treatment of rheumatoid arthritis (RA), as well as recent advances.Data Sources:MEDLINE search from 1990 to 1998 for human studies using search terms “rheumatoid arthritis”; “cyclooxygenase inhibitors” combined with “anti-inflammatory agents, nonsteroidal”; “tumor necrosis factor” limited to “antagonists and inhibitors”; “isoxazoles.”Data Synthesis:RA is a chronic inflammatory disease characterized by symmetrical joint involvement, usually of the small joints of the hands and feet. Although the hallmark of the disease is inflammation of joints, other organ systems—including the eyes, blood vessels, lungs, and car-diopulmonary system—may also be involved. Treatment of RA requires both drug and non drug approaches. Current drug therapy consists of combinations of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). Corticosteroids are also used either for short-term treatment during initiation of therapy, in bursts during acute disease flares, or chronically in low doses. A number of promising new agents are in development. NSAIDs with preferential inhibition of cyclooxygenase II may offer a better safety profile than existing agents. Leflunomide and biological agents such as etanercept may provide benefit for patients who fail to achieve adequate response from conventional therapy.Conclusion:Traditional approaches to treatment of RA include NSAIDs combined with DMARDs. New agents just reaching the market represent important advances and have the potential to make a positive impact on treatment of RA.     

A pathogenetic approach to autoimmune skin disease therapy: psoriasis and biological drugs, unresolved issues, and future directions

Psoriasis is a chronic inflammatory disease with a complex pathophysiology and a multigenic background. Autoimmunity and genetic hallmarks couple to confer the disease, which is characterized by chronic plaques (85-90% of all cases) and/or psoriasis arthritis (PsA), and involve the peripheral and sacro-iliac joints, nails, and skeleton. Dissecting the ethiopathogenetic mechanisms of psoriasis and PsA is a major basic research challenge. One important question is whether a single inflammatory mediator can be responsible for the interactive network that forms between immune cells and cytokines in this disease. Despite much progress, no research has yet been able to define a single model to explain the multifaceted pathogenesis of psoriasis and PsA. It is known that both the innate and adaptive immune systems are involved, antigen presenting cells and T lymphocytes play a prominent role, and that the deregulation of the T helper (Th)- 1/Th-2/Th-17/Th-23 axis is directly implicated in disease pathogenesis. Pharmacological therapy for psoriasis has evolved with the development of human knowledge of the disease pathophysiology. Thus, the first "ethiopathogenetic" drugs (e.g., methotrexate, cyclosporin, and alefacept) inhibited T-cell activation directly or targeted co-accessory molecules implicated in T-cell activation. When the mechanism underlying psoriatic inflammation was accepted as a cytokine network disorder, more specific biologics were studied in murine models and were later used clinically. Tumor necrosis factor was the first successful target of cytokine inhibition therapy for psoriasis and PsA (e.g., infliximab, adalimumab, and etanercept). With the recently discovered role for Th-17 in autoimmunity, drugs targeting interleukin-23 (ustekinumab) have become accepted for the pharmacological treatment of psoriasis. The expansion of pharmacological treatment options for psoriasis is not complete. As the knowledge of pathogenetic mechanisms increases, it may be possible to design therapeutic approaches that selectively target the ethiopathogenetic cells or cytokines while sparing the others. In this way, using a more targeted drug therapy may preserve the integrity of the immune system. Thus, one great struggle in treating this complex disease is the challenge to synthesize the "perfect" drug.     

New drugs for peripheral joint psoriatic arthritis

Up to 3% of people have psoriasis, and as many as 42% of these have an associated chronic inflammatory arthritis. In up to 20% of such patients, the arthritis progresses to become severe, destructive and deforming. Traditional drug treatments include NSAIDs and disease-modifying anti-rheumatic drugs (DMARDs) used for rheumatoid arthritis. Leflunomide (Arava - Sanofi-Aventis), etanercept (Enbrel - Wyeth) inifliximab (Remicade - Schering-Plough) and adalimumab (Humira - Abbott) are licensed for the treatment of patients with peripheral joint disease in psoriatic arthritis. Here we review drug therapy for such patients, concentrating on the newer agents.     

Chinese herbs as immunomodulators and potential disease-modifying antirheumatic drugs in autoimmune disorders

Autoimmune diseases are a group of illnesses with multiple organ involvement. The prototype of this group of disorders is rheumatoid arthritis (RA) that aside from systemic organ involvement mainly presents with progressive destruction of many joints. Both activation and defective apoptosis of immune effector cells like T and B lymphocytes and macrophages play critical roles in the pathogenesis of autoimmune disorders. Current therapy for autoimmune diseases recommends a combination of several disease-modifying antirheumatic drugs (DMARDs) that preserve different immunomodulatory mechanisms. Because of limited success in prevention of RA joint destruction for currently available DMARDs, the development of more effective and less toxic DMARDs has been one of the major goals for pharmaceutical companies. The introduction of leflunomide and anti-tumor necrosis factor alpha therapies to the market recently serves as examples. In this context, the experience from ancient Chinese medicine gives an alternative consideration looking for potential DMARDs. Two commonly prescribed Chinese antirheumatic herbs are Tripterygium wilfordii hook f (TWHf) and tetrandrine (Tet) that preserve both anti-inflammatory and immunosuppressive effects. Importantly, the TWHf- or Tet-mediated immunomodulatory mechanisms are evidently different from the known DMARDs. The synergistic effects have also been demonstrated between these two Chinese antirheumatic herbs and DMARDs like FK506, cyclosporin and possibly chloroquine. Another potential Chinese herb for this consideration is Ginkgo biloba. This review summarizes evidence-based in vivo and in vitro studies on Chinese herbs as immunomodulators and potential DMARDs.     

Emerging drugs for psoriatic arthritis

Importance of the field: The socioeconomic burden of psoriatic arthritis (PsA) is considerable and not different from that of rheumatoid arthritis. Current treatment options do not always allow reaching the therapeutic objectives consisting of the remission of symptoms and prevention of the appearance of damage in the early stage of PsA or the blocking of PsA progression in the established cases.

Areas covered in this review: After reviewing the current treatment choices, we examine the new drugs in clinical Phase II and III trials for PsA up to January 2010. Information was mainly obtained from the network of international clinical trial registries.

What the reader will gain: The current management of PsA includes NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs) and anti-TNF-α blocking agents. These last drugs are more effective than traditional DMARDs on symptoms/signs of inflammation, quality of life and function and can inhibit the progression of the structural joint damage. Recent advancement in the knowledge of the immunopathogenesis of PsA has permitted the development of novel drugs including new TNF-α blockers, IL-1, -6, -12, -23 and -17 inhibitors, co-stimulator modulation inhibitors, B-cell depleting agents, small molecules and receptor activator of NF-κB/receptor activator of NF-κB ligand inhibitors.

Take home message: The currently available anti-TNF-α blocking agents have revolutionized the management of PsA. However, there is a need for more effective and safer drugs.     

Pharmacogenetics of therapies in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory, aggressive arthritis causing irreversible joint destruction and damage when left untreated. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment for RA and ameliorate not only the clinical signs and symptoms but also joint damage associated with the disease. In recent years, biological therapies have been introduced for the treatment of RA, and the effectiveness of these agents in slowing the clinical and radiographic progression in RA has been established beyond question. However, there is significant variability in the response of patients with RA to these therapies. Moreover, the biological therapies are expensive, totaling several thousand dollars in yearly patient costs. Pharmacogenomics, the study of genetic variations in drug-metabolizing enzymes and their translation to differential responses to drugs, is a nascent but rapidly evolving field. The application of pharmacogenomics to therapies used in RA, particularly the new expensive biological agents, holds great promise for tailoring therapy with these agents based on a patient's genetics. Published literature on the pharmacogenetics of commonly used DMARDs and the emerging body of literature on the pharmacogenetics of the new biological therapies in RA are the focus of this review. As evident from the contents of this review, pharmacogenomics is an exciting field which is progressing productively and rapidly. Pharmacogenomic approaches offer powerful tools to optimize drug therapy in individual patients.