Psoriatic arthritis (PsA) is a chronic, progressive, inflammatory spondyloarthropathy that affects approximately one-third of patients with all types of psoriasis. Dermatologists are in a unique position to recognize early symptoms of PsA, initiate appropriate therapy, and prevent development of further disability. The course of PsA can be modulated by immunosuppressive therapy; patients with moderate-to-severe disease require aggressive management with medications proven to halt disease progression. It is essential for the dermatologist to understand the safety, tolerability, efficacy, cost, and potential to halt disease progression with available medications for this relatively common and potentially disabling disease.
Key points
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Psoriatic arthritis (PsA) is underdiagnosed and undertreated, and dermatologists are in a unique position to recognize symptoms of the disease early and initiate disease-modifying therapy before significant effects on patients’ quality of life and functional capacity occur.
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All patients with psoriasis require screening for PsA.
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Characteristics of PsA include enthesitis, dactylitis, spondylitis and sacroiliitis, stiffness after inactivity, and involvement of the distal interphalangeal joints and nails.
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Joint damage begins early in the course of the disease, and a tumor necrosis factor α inhibitor is required to halt progression of synovitis, bone resorption, formation of osteophytes, enthesitis, and dactylitis.
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Apremilast and tofacitinib are promising new orally administered medications for PsA.
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The interleukin (IL)-17 inhibitors and IL-23p19 inhibitors have been developed in response to improved understanding of the immunopathogenesis of PsA and osteoclastogenesis; these targeted therapies have shown excellent efficacy in PsA in early investigational studies.
Overview: nature of the problem
Psoriatic arthritis (PsA) is an underdiagnosed, undertreated, chronic, progressive spondyloarthropathy occurring in 11% to 42% of patients with cutaneous psoriasis. Similar to psoriasis, PsA affects men and women equally, and usually develops between the ages of 30 and 50 years, although it can develop in childhood. Patients with PsA have significantly impaired physical functioning and quality of life (QOL), with high rates of anxiety, depression, and poor self-image. The disease is characterized by flares and remissions; but only about 18% of patients will experience sustained periods of remission, lasting on average 2.5 years. Many patients with PsA are undertreated or are not treated systematically. For instance, in Lebwohl and colleagues’ 2014 multinational study, approximately 15% of patients with PsA had not seen a health care provider in the past year, and almost 60% were not being treated for their joint disease.
Our understanding of the immune dysregulation that triggers psoriatic pathophysiology has greatly improved over the past 20 years and has driven the development of targeted therapies for psoriasis and PsA. Innate and adaptive immune responses are abnormally activated in PsA, and, in genetically susceptible patients, may acquire the ability to attack peripheral joints and other sites following an environmental trigger or inciting event (eg, mechanical stress and trauma including microtrauma). PsA is highly heritable: In a 2009 study, 7.6% of first-degree relatives of patients with PsA also had PsA (17.7% of first-degree relatives had psoriasis). Genome-wide studies have identified important risk loci for the disease; the psoriasis susceptibility 1 locus ( PSORS1 ) was among the first identified and mapped to the major histocompatibility complex class I region. The presence of the HLA-Cw*0602 allele accounts for an estimated one-third to one-half of genetic susceptibility to psoriasis, whereas the human leukocyte antigen (HLA)-B27, HLA-B38, and HLA-B39 alleles are more highly associated with PsA (specifically, HLA-B27 is linked to spinal involvement, and HLA-B38 and HLA-B39 to peripheral polyarthritis). A strong genetic association of PsA with variants of the interleukin (IL)-23 receptor (IL-23R) and the IL-23p40 subunit has also been demonstrated, implicating the central pathophysiologic function of the IL-23/IL-17 axis in triggering the joint inflammation and downstream effects seen in the disease.
PsA is characterized by inflammation of the tendons, ligaments, synovia, and bone, with the development of focal bone erosions mediated by osteoclasts at the bone-pannus junction. Histopathologically, PsA displays an influx of Th17 cells, a thin layer of synovial epidermal hyperplasia, and increased levels of proinflammatory, osteoclastogenic cytokines. This cytokine milieu includes elevated levels of tumor necrosis factor (TNF)-α, IL-1B, IL-17, IL-12, IL-23, interferon-γ (IFN-γ), and receptor activator of NF-kappa B ligand (RANKL), together acting as potent inducers of the proliferation and activation of synovial and epidermal fibroblasts. Long-term inflammation at this site leads to bone erosions alongside new bone formation in the form of syndesmophytes, enthesophytes, and ankylosis (peripheral bony fusion). IL-23 is a crucial upstream mediator of this process. Comprising a specific p19 subunit and a p40 subunit which it shares with IL-12, IL-23 is a mucosal defense factor derived from resident lymphoid or epidermal cells in the skin that acts synergistically with IL-6 and transforming growth factor β1 to promote rapid Th17 development, potentiating IL-17 and IL-22 release. Mouse models of spondyloarthropathy have shown that early features of bone remodeling (early enthesitis, arthritis, and bone formation) are ameliorated by the addition of anti–IL-23 antibodies. Following induction by IL-23, IL-17 and IL-22 stimulate proliferation of synovial fibroblasts and subsequent joint inflammation, and STAT-3 (signal transducer and activator of transcription 3) dependent osteoblast-mediated bone remodeling. In addition to induction of enthesitis and synovial hyperplasia, IL-17 and IL-23 are associated with changes in the RANKL-RANK axis, which further increases osteoclast formation and promotes bone remodeling in PsA. Further knowledge regarding how simultaneous bone formation and bone resorption in PsA occurs, and how the osteoclast-osteoblast homeostasis becomes dysregulated in the psoriatic joint, is required and will further guide therapeutic development. IL-33, which may abrogate the effects of TNF-α on the RANKL pathway, and drugs inhibiting IL-1 and Bruton tyrosine kinase, both of which are costimulatory signals for osteoclastogenesis, are additional targets being studied that may have potential in PsA treatment.
Juvenile psoriatic arthritis (JPsA) has traditionally been considered a subset of juvenile idiopathic arthritis (JIA), representing about 7% of all JIA cases. JPsA epidemiologically, pathologically, and clinically manifests similarly to adult PsA. As in adults, cutaneous psoriasis may not be present and joint symptoms may significantly precede cutaneous disease. Treatment options for JPsA are discussed within each medication section that follows.
Overview: nature of the problem
Psoriatic arthritis (PsA) is an underdiagnosed, undertreated, chronic, progressive spondyloarthropathy occurring in 11% to 42% of patients with cutaneous psoriasis. Similar to psoriasis, PsA affects men and women equally, and usually develops between the ages of 30 and 50 years, although it can develop in childhood. Patients with PsA have significantly impaired physical functioning and quality of life (QOL), with high rates of anxiety, depression, and poor self-image. The disease is characterized by flares and remissions; but only about 18% of patients will experience sustained periods of remission, lasting on average 2.5 years. Many patients with PsA are undertreated or are not treated systematically. For instance, in Lebwohl and colleagues’ 2014 multinational study, approximately 15% of patients with PsA had not seen a health care provider in the past year, and almost 60% were not being treated for their joint disease.
Our understanding of the immune dysregulation that triggers psoriatic pathophysiology has greatly improved over the past 20 years and has driven the development of targeted therapies for psoriasis and PsA. Innate and adaptive immune responses are abnormally activated in PsA, and, in genetically susceptible patients, may acquire the ability to attack peripheral joints and other sites following an environmental trigger or inciting event (eg, mechanical stress and trauma including microtrauma). PsA is highly heritable: In a 2009 study, 7.6% of first-degree relatives of patients with PsA also had PsA (17.7% of first-degree relatives had psoriasis). Genome-wide studies have identified important risk loci for the disease; the psoriasis susceptibility 1 locus ( PSORS1 ) was among the first identified and mapped to the major histocompatibility complex class I region. The presence of the HLA-Cw*0602 allele accounts for an estimated one-third to one-half of genetic susceptibility to psoriasis, whereas the human leukocyte antigen (HLA)-B27, HLA-B38, and HLA-B39 alleles are more highly associated with PsA (specifically, HLA-B27 is linked to spinal involvement, and HLA-B38 and HLA-B39 to peripheral polyarthritis). A strong genetic association of PsA with variants of the interleukin (IL)-23 receptor (IL-23R) and the IL-23p40 subunit has also been demonstrated, implicating the central pathophysiologic function of the IL-23/IL-17 axis in triggering the joint inflammation and downstream effects seen in the disease.
PsA is characterized by inflammation of the tendons, ligaments, synovia, and bone, with the development of focal bone erosions mediated by osteoclasts at the bone-pannus junction. Histopathologically, PsA displays an influx of Th17 cells, a thin layer of synovial epidermal hyperplasia, and increased levels of proinflammatory, osteoclastogenic cytokines. This cytokine milieu includes elevated levels of tumor necrosis factor (TNF)-α, IL-1B, IL-17, IL-12, IL-23, interferon-γ (IFN-γ), and receptor activator of NF-kappa B ligand (RANKL), together acting as potent inducers of the proliferation and activation of synovial and epidermal fibroblasts. Long-term inflammation at this site leads to bone erosions alongside new bone formation in the form of syndesmophytes, enthesophytes, and ankylosis (peripheral bony fusion). IL-23 is a crucial upstream mediator of this process. Comprising a specific p19 subunit and a p40 subunit which it shares with IL-12, IL-23 is a mucosal defense factor derived from resident lymphoid or epidermal cells in the skin that acts synergistically with IL-6 and transforming growth factor β1 to promote rapid Th17 development, potentiating IL-17 and IL-22 release. Mouse models of spondyloarthropathy have shown that early features of bone remodeling (early enthesitis, arthritis, and bone formation) are ameliorated by the addition of anti–IL-23 antibodies. Following induction by IL-23, IL-17 and IL-22 stimulate proliferation of synovial fibroblasts and subsequent joint inflammation, and STAT-3 (signal transducer and activator of transcription 3) dependent osteoblast-mediated bone remodeling. In addition to induction of enthesitis and synovial hyperplasia, IL-17 and IL-23 are associated with changes in the RANKL-RANK axis, which further increases osteoclast formation and promotes bone remodeling in PsA. Further knowledge regarding how simultaneous bone formation and bone resorption in PsA occurs, and how the osteoclast-osteoblast homeostasis becomes dysregulated in the psoriatic joint, is required and will further guide therapeutic development. IL-33, which may abrogate the effects of TNF-α on the RANKL pathway, and drugs inhibiting IL-1 and Bruton tyrosine kinase, both of which are costimulatory signals for osteoclastogenesis, are additional targets being studied that may have potential in PsA treatment.
Juvenile psoriatic arthritis (JPsA) has traditionally been considered a subset of juvenile idiopathic arthritis (JIA), representing about 7% of all JIA cases. JPsA epidemiologically, pathologically, and clinically manifests similarly to adult PsA. As in adults, cutaneous psoriasis may not be present and joint symptoms may significantly precede cutaneous disease. Treatment options for JPsA are discussed within each medication section that follows.
Patient evaluation
Patients with PsA typically present with an inflammatory arthritis, have a personal or family history of psoriasis, and are seronegative for rheumatoid factor. The clinical spectrum of PsA includes 5 major components, although not all are necessary for diagnosis: peripheral arthritis; axial disease/spondylitis; skin disease; dactylitis; and enthesitis. Approximately 50% to 60% of patients have peripheral arthritis only, 6% have spondylitis only, and 35% to 40% have both peripheral arthritis and spondylitis. Pain and stiffness are usually worse with rest and improved with activity, and patients may complain of morning stiffness (often >30 minutes in duration). Joint symptoms typically improve with activity but can present, regardless of activity level, as inflamed, warm, tender, and swollen, with limited range of motion. Dystrophy of the fingernails and/or toenails (eg, onycholysis, pitting, oil spots, hyperkeratosis, leukonychia, and/or nail plate crumbling) is strikingly common in PsA: up to 87% of PsA patients will present with this component of disease. Risk factors for the development of PsA include: scalp involvement, increased extent of body surface area psoriasis plaque involvement, increased duration of psoriasis, presence of nail disease, intergluteal/perianal involvement, and increased body mass index. In patients with psoriasis, skin symptoms are present for an average of 12 years before joint symptoms. Thus, dermatologists are in a unique position to recognize and diagnose PsA early in the course of disease and initiate disease-modifying therapy before musculoskeletal destruction progresses to irreversible damage. All patients with psoriasis should be screened for PsA.
Each of the peripheral and axial joints should be assessed for stiffness, tenderness, and swelling, with careful attention particularly to the hands and feet, which are frequently involved. Enthesitis, disease at the site of insertion of tendon, ligament, or joint capsule fibers into the bone, may be the sole manifestation of PsA and is seen most commonly at the insertion sites of the plantar fascia, the Achilles tendon, as “tennis elbow,” and at attachment sites of ligaments to the ribs, spine, and pelvis. Dactylitis, the combination of inflammation of the soft tissue, tendons, and/or ligaments and synovial lining of the joint, resulting in a “sausage digit” appearance of the affected digit, occurs in about one-fifth of patients with PsA. The distal interphalangeal joints (DIPs) are commonly affected in PsA, involved in about 41% of patients, and are frequently accompanied by psoriasis nail changes. The knee is the most commonly affected joint in PsA monoarthritis, and the spine is most often affected at the lumbosacral transition and the neck. Involvement of sacroiliac joints (sacroiliitis) typically presents as asymmetric back pain and stiffness in the morning.
The American College of Rheumatology (ACR) 68 tender joint and 66 swollen joint assessment, developed for rheumatoid arthritis (RA), may be used as a guideline in PsA, although it is mostly used for outcome studies. This evaluation includes the DIPs and the feet, and has shown minimal intraobserver and interobserver variation in PsA studies. The temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist (including the carpometacarpal and intercarpal joints as one unit), metacarpophalangeal (MCP), proximal interphalangeal (PIP), DIP, hip, knee, talotibial, midtarsal (including subtalar), metatarsophalangeal, and interphalangeal joints of the toes are each evaluated. As it may be difficult to distinguish between PIP and DIP joint inflammation of the toes, inflammation of the PIP or DIP of the toe is counted as one unit. Consideration of cutaneous disease is as important in the evaluation and choice of medication in PsA patients. A full body skin examination to evaluate the severity of current psoriasis, optimally with determination of body surface area of involvement with use of the Psoriasis Area and Severity Index (PASI), should be performed in all patients.
Radiographic evaluation to examine osteitis, bone erosions, and new bone formation is typically performed by rheumatologists to aid in the differential diagnosis of PsA, although results affect the dermatologist’s choice of therapy, as only the TNF-α inhibitors and ustekinumab have been found to delay radiographic disease progression. Additional radiographic findings in PsA are joint erosion, joint narrowing, new bone growth (including spur formation, spondylitis, “flail” or ankylotic deformities of the digits, and syndesmophytes), and/or profound phalangeal osteolysis (“pencil-in-cup” deformity). Ultrasonographic examination may also be performed by rheumatologists to further evaluate enthesitis, which can be difficult to assess on both clinical examination and conventional radiography.
Diagnosis of PsA should be based on the modified CASPAR (ClASsification criteria for Psoriatic Arthritis) criteria ( Table 1 ), in which a patient with musculoskeletal symptoms (arthritis, enthesitis, and/or spondylitis) meets at least 3 points from the criteria shown in Table 1 . The CASPAR criteria have a high specificity and sensitivity for diagnosing PsA.
| Criterion | Point Value |
|---|---|
| Current psoriasis | 2 |
| Personal history of psoriasis (unless current psoriasis is present) | 1 |
| Family history of psoriasis (unless current psoriasis is present or there is a personal history of psoriasis) | 1 |
| Dactylitis (current or personal history) | 1 |
| Juxta-articular new bone formation | 1 |
| Rheumatoid factor negativity | 1 |
| Nail dystrophy (onycholysis, pitting, and/or hyperkeratosis) | 1 |
Patients should be advised of certain environmental factors that have been implicated in the pathogenesis of both psoriasis and PsA, and may lead to flare of the latter. Mainly physical trauma/injury and emotional stress have been shown to drive inflammatory pathways in both psoriasis and PsA. Both increased body mass index and smoking are risk factors for PsA and are associated with increased severity of PsA; thus, increases in body weight in addition to increased or new smoking may be expected to flare disease.
Following clinical evaluation of the joints and skin, patient QOL and loss of function attributable to PsA should be assessed. Patients with hand and/or foot involvement can have severely impaired ability to perform activities of daily living. All patients should be educated as to the nature of their condition and to the effect of stress on their disease. Rates of depression and anxiety are high (prevalence rates range from 19.2% to 62%) in patients with all types and severities of psoriatic disease. Furthermore, patients with PsA have been found to have a worse QOL than patients with psoriasis alone, and the presence of joint pain is associated with higher rates of depression. In a 2014 study of 306 patients with PsA, the prevalence of depression and anxiety were approximately 22.2% and 36.6%, respectively. There are variable results on the association of PsA treatment with a decrease in prevalence of anxiety and/or depression in PsA patients. Depression and anxiety symptoms may be less likely to improve with psoriatic disease treatment in patients with PsA compared with patients with psoriasis alone, which highlights the value of identifying PsA patients with symptoms of psychiatric illness and applying a multidisciplinary approach.
All patients should be evaluated for the presence of comorbidities associated with psoriasis and PsA (diabetes, obesity, metabolic syndrome, nonalcoholic fatty liver disease [NAFLD], coronary artery disease, cerebral artery disease, depression) that may affect overall health and selection of treatment. In evaluating the patient’s medical history, particular attention should also be given to the presence of liver disease including a history of hepatitis B or hepatitis C, impaired renal function, congestive heart disease, a personal or family history of demyelinating disease, anemia and other cytopenias, personal history of malignancy, history of tuberculosis and other chronic, serious infections. In patients with liver enzyme levels greater than 3 times the upper limit of normal, an ultrasonogram of the liver should be performed to evaluate for NAFLD and other causes of liver disease, which may preclude the patient from receiving certain medications. Laboratory evaluation of erythrocyte sedimentation rate and C-reactive protein (CRP), which are elevated in about 50% of PsA patients, may be used for prognostic reasoning and to monitor disease activity, but are nonspecific for PsA and generally do not contribute to choice of medical therapy nor to determination of disease severity.
Management goals
Improving joint pain and soreness, mobility, patient QOL, and emotional health are major goals for PsA patients, ideally through management by both a dermatologist and rheumatologist. Treatment of cutaneous disease alone is insufficient and has little effect on joint symptoms of PsA. Treatment algorithms for PsA have been suggested by the European League Against Rheumatism (EULAR) (most recently, in 2013) and by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), most recently in 2009. The authors recommend that patients with severe disease, examples of whom are given in Box 1 , receive treatment with a biological agent as first-line therapy. Although PsA should not be defined by the number of joints involved alone but in combination with patient QOL and functional status, in general, patients with 2 or more swollen joints and 2 or more tender/painful joints, or with sacroiliitis or spondylitis in 1 or more joint have at least moderate PsA and may be candidates for a TNF-α inhibitor, ustekinumab, apremilast, or combination therapy.
Presence of 3 or more swollen and tender joints causing functional disability
Axial joint involvement
Moderate-to-severe cutaneous psoriasis (high Psoriasis and Area Severity Index [PASI] score and joint disease with a severely affected quality of life)
Presence of enthesitis or dactylitis unresponsive to nonsteroidal anti-inflammatories, intra-articular corticosteroids, and/or disease-modifying antirheumatics
Axial involvement of PsA presents a unique treatment challenge. Data on adequacy of available medications has been adapted from ankylosing spondylitis (AS) studies, and have not been adequately studied in PsA. However, each of the available TNF-α inhibitors has shown significant improvements in axial spondyloarthropathy in AS; response rates were similar, averaging at about 60%. Ustekinumab also has promise for effectiveness in treating axial disease: A 2014 open-label trial on the use of ustekinumab in 24 patients with AS found an improvement in BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) of at least 50% in 55% of patients.
In addition to improving patient QOL, mobility, and functional capability, dermatologists need to encourage patient medication compliance, even in the absence of symptoms, to prevent disease flares.
Pharmacologic treatment options
PsA therapy has historically relied on the nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs), but these agents are not ideal because of long-term potential toxicity. The TNF-α inhibitors and ustekinumab are the mainstay for moderate-to-severe PsA in preventing disease progression and slowing joint damage. However, given practical and financial restraints, patients are often placed on methotrexate (MTX) or another DMARD before initiation of a biologic.
Mild PsA (simple enthesopathy alone, or involvement of one joint that does not affect QOL or functioning) may be treated with NSAIDs, which reduce inflammation through nonselective inhibition of cyclo-oxygenase enzymes COX1 and COX2, thereby preventing formation of proinflammatory prostaglandins and leukotrienes, and/or with intra-articular glucocorticoid injections. Enteric-coated aspirin, naproxen, ibuprofen, diclofenac, or ketoprofen are used for peripheral arthropathy, and indomethacin or tolmetin are often chosen for axial disease. NSAIDs are associated with a high rate of adverse events: Endoscopic studies indicate that gastric or duodenal ulcers develop in 15% to 30% of patients who regularly take NSAIDs, and the medications attenuate the efficacy of certain antihypertensive agents. Rarely, NSAIDs may lead to flaring or exacerbation of psoriasis.
Rheumatologists often perform intra-articular injections of glucocorticoids for PsA that is either mild or limited to only 1 or 2 joints. Repetitive intra-articular glucocorticoid injection is safe and has good efficacy in the short term: McCarty reported that 88% of patients receiving intra-articular glucocorticoid injection in the small joints of the hands and/or wrists achieved relative remission with symptomatic control lasting an average of 22 months. Doses of glucocorticoid used in PsA are based on the standards for RA. Repetitive glucocorticoid injections may be particularly valuable as a nonsystemic treatment of pauciarticular-onset JIA. Systemic corticosteroids are seldom used by dermatologists for the treatment of PsA, given the risk of potentially severe cutaneous disease flare, particularly pustular psoriasis. In patients with little or no psoriasis, some rheumatologists use low-dose prednisone (5–10 mg) for long-term treatment of mild PsA.
Disease-Modifying Antirheumatic Drugs
MTX is the most commonly used oral drug for PsA in clinical practice. It competitively inhibits the enzyme dihydrofolate reductase, necessary for synthesis of nucleic acids; significant lymphoid tissue proliferation also occurs with MTX treatment. Of note, MTX is more efficacious in joint disease than in skin disease, and may be one of the better options for a patient with PsA without cutaneous psoriasis or with severe PsA and only mild skin symptoms. Two randomized, placebo-controlled studies of MTX (15 mg/wk) in PsA found significant improvements in global assessment ratings with treatment, although tender and swollen joint counts and composite measures of PsA (PsARC, ACR20, and DAS28) did not improve in either study at 3 or 6 months. MTX has demonstrated good retention rates (approximately 65% at 2 years).
Oral MTX has an advantage in that it is only given once a week, at doses ranging from 7.5 to 25 mg weekly as a single dose or divided into 3 doses within a 24-hour period. Recommendations for testing before initiating treatment are the same as that in psoriasis or other diseases: Before MTX initiation, a complete blood count with differential, chemistry panel, hepatitis panel, tuberculosis testing, and a pregnancy test should be performed. A low-level test dose may be given to evaluate for bone marrow suppression in susceptible patients.
Once an adequate dose is reached, patient response can take 4 to 6 weeks. Folic acid, which can prevent elevations in liver enzymes, is usually prescribed once weekly to 6 days a week (there are no randomized controlled trials to determine the optimal dose). Slow tapering of MTX in patients who do not respond after 6 to 8 weeks of therapy is recommended to prevent potentially severe flares of both skin and joint disease.
Common toxicities of MTX are nausea, anorexia, stomatitis, and fatigue (typically at the time of administration), effects that can be minimized by splitting the dose throughout the day of administration and administering the drug with food. The most serious potential side effects of MTX include liver toxicity, interstitial lung disease, and bone marrow suppression. Complete blood counts and chemistry panels with liver function enzymes and albumin should be monitored once every 2 to 4 weeks during the first few months of treatment (and when treatment doses are increased), then once every 1 to 3 months. Monitoring guidelines for hepatotoxicity are given in Box 2 . In psoriasis patients, the risk of hepatic fibrosis has been most common in patients with additional risk factors for liver disease (obesity, diabetes, and alcohol use).
| Patients at low risk for liver disease | |
| Monitor LFTs monthly for the first 6 months of treatment, then once every 1 to 3 months thereafter |
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| First biopsy at 3.5 to 4 g total cumulative dose; subsequent biopsies to be considered at additional 1.5 g of drug |
|
| Patients at high risk for liver disease | |
| Baseline biopsy, then subsequent biopsies every 6 months or with after additional 1 to 1.5 g of drug | |
| Risk factors for liver disease | |
| Personal history of diabetes mellitus, obesity, persistent abnormal LFT results, history of or current excessive alcohol consumption, history of chronic liver disease including hepatitis B or C, family history of inheritable liver disease, history of significant exposure to hepatotoxic drugs or chemicals, lack of folate supplementation, hyperlipidemia | |
MTX is Food and Drug Administration (FDA) pregnancy category X and is contraindicated in women trying to conceive. Its use in pediatric PsA patients has primarily been evaluated in JIA, and low-dose weekly MTX has been highly effective, safe, and well tolerated in this pediatric population; primary side effects are similar to those seen in adults, and adult liver biopsy guidelines may be followed. According to the ACR 2011 recommendations, a course of MTX is recommended for children with high disease activity and features of poor prognosis, or if they have failed intra-articular glucocorticoid injections.
Leflunomide, an inhibitor of de novo pyrimidine synthesis, is approved for use in RA, and is less frequently used and not FDA-approved in the treatment of psoriasis and PsA. However, leflunomide has shown efficacy equivalent to that of MTX in randomized, double-blind, placebo-controlled studies in PsA: In a 2013 multicenter European study of 514 patients treated with leflunomide for PsA, PsARC response was achieved by 86% of the patients at week 24, and significant improvement was seen in tender and swollen joint counts, dactylitis, nail lesions, skin lesions, and patient self-assessment. Other studies have found significantly lower response rates: A 2004 randomized controlled study of patients with PsA in the United States found that 59% of patients were receiving leflunomide according to the PsARC. Diarrhea and increased serum aminotransferase levels are adverse effects of the drug that are well described in RA trials. Leflunomide can be considered for patients who fail MTX treatment or in whom an oral medication is required. It is given in a loading dose of 100 mg/d for 3 days followed by 20 mg/d thereafter, and is associated with gastrointestinal upset, weight loss, headache, dizziness, elevated liver enzymes, leukopenia, and an increased risk of infections. The drug is teratogenic and its use has not been studied in the pediatric PsA population, although it is effective in pediatric RA.
Similar to leflunomide, sulfasalazine is not FDA-approved for the treatment of either psoriasis or PsA, but several double-blind, placebo-controlled studies of the drug in both psoriasis and PsA have shown that it is moderately effective (dosages escalated over time as tolerated from 1.5 to 4.0 g daily). It is thought to exert anti-inflammatory effects through inhibition of the 5-lipoxygenase pathway. Adverse effects associated with sulfasalazine include gastrointestinal disturbances, arthralgias, reversible oligospermia, leukopenia, and agranulocytosis. Sulfasalazine is FDA pregnancy category B and has been used rarely, but safely and efficaciously, in the pediatric population. Before instituting therapy with sulfasalazine, it is important to ascertain that the patient does not have an allergic history to sulfa drugs.
Cyclosporine A (CsA) is a rapidly acting immunosuppressive agent FDA-approved for severe, recalcitrant psoriasis. The drug binds to cyclophilin, subsequently inhibiting calcineurin and its downstream proinflammatory signal pathways that lead to T-cell activation. In PsA, CsA is used in low doses (typically 2.5–5 mg/kg/d). In a 2001 open-label study of patients with PsA, CsA was significantly better than both sulfasalazine alone and “usual care” (prednisone, NSAIDs, and analgesics) in decreasing pain and cutaneous lesions. In reducing tender and swollen joint counts, CsA was similarly effective as sulfasalazine and significantly more effective than usual care.
CsA is particularly useful in crisis management of psoriasis; comparative studies have found greater efficacy of CsA in comparison with MTX in psoriasis, including in patients with PsA. However, owing to its side effects of nephrotoxicity and hypertension, use of CsA should not exceed 12 months to prevent irreversible renal damage. Before initiation of the drug, 2 blood pressure readings, 2 serum creatinine measurements, a complete blood count, a complete chemistry panel with magnesium, and a lipid panel are performed, and monitoring is recommended every other week after initiation of treatment, then once every 1 to 3 months. Additional side effects of CsA include hypomagnesemia, hyperkalemia, hyperlipidemia, drug-to-drug interactions, hypertrichosis, and lymphoproliferative disease. The FDA has classified CsA as category C; it should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. CsA use in JPsA has been reported only rarely, although its use in children with other dermatologic and rheumatologic conditions suggests that the side effect profile is similar to that seen in adults.
Tumor Necrosis Factor α Inhibitors
TNF-α plays a pivotal role in the chronic inflammation underlying PsA and psoriasis, and the TNF-α inhibitors have revolutionized therapy for PsA. TNF-α inhibitors etanercept, infliximab, and adalimumab are remarkably effective in psoriasis and have become first-line for patients with moderate-to-severe PsA. Of note, the TNF-α inhibitors etanercept, infliximab, adalimumab, and golimumab are efficacious in improving enthesitis and dactylitis, and can markedly inhibit radiographic progression of disease. Recommended dosages of the TNF-α inhibitors and their respective PsA and psoriasis response rates are given in Table 2 . Importantly, although TNF-α inhibitors have great benefits for many patients with psoriasis, their efficacy is not universal and the magnitude and durability of their effect is variable.
| Biologic a | Recommended Dose in PsA | % Achieving ACR20 | % Achieving PASI-75 | Beneficial Effect on Radiographic Damage | Adverse Effects |
|---|---|---|---|---|---|
| Etanercept: Anti-TNF agent; recombinant fusion protein of p75 unit of TNF receptor and Fc portion of human IgG1 | 25 or 50 mg SubQ twice weekly | 59% (week 24) | 26% of PsA patients (week 24) 49% of Ps patients (week 12) | Yes | Pruritus Headache Immunosuppression Injection-site reaction |
| Adalimumab: Anti-TNF agent; Fully human monoclonal antibody | 40 mg SubQ every 2 wk | 58% (week 24) | 59% of PsA patients (week 24) 76% of Ps patients (week 160) | Yes | Immunosuppression |
| Infliximab: Anti-TNF agent; chimeric mouse/human antibody | Initial: 5 mg/kg IV infusion at weeks 0, 2, and 6; Maintenance: 5 mg/kg IV infusion every 8 wk | 65% (week 16) | 65% of PsA patients 80% of Ps patients (week 10) | Yes | Lupus-like symptoms Serum sickness/delayed reactions Infusion reactions Elevated liver enzymes |
| Golimumab: Anti-TNF agent; fully human monoclonal antibody | 50 mg SubQ every 4 wk | 51% (week 256) | 62.8%–69.9% of PsA patients (week 256) 60.8%–72.2% of Ps patients (week 256) | Yes | Headache Nasopharyngitis Increased risk of nonmelanoma skin cancers Immunosuppression |
| Certolizumab pegol: Anti-TNF agent; pegylated fully human monoclonal antibody | Initial: 400 mg SubQ, at weeks 0, 2 and 4; Maintenance: 200 mg every 2 wk | 58.0% (week 12) | 62.2% of PsA patients (week 24) 75%-83% of Ps patients (week 12) | Yes | Headache Nasopharyngitis Diarrhea URI Immunosuppression Elevated liver enzymes |
| Ustekinumab: Anti-IL12/23p40 | 45 or 90 mg SubQ every 12 wk | 42% receiving 45 mg (week 16) 49.5% receiving 90 mg (week 16) | 62% of PsA patients (week 16) 74% of Ps patients (week 12) | Yes | Increased risk of infection Headache Upper respiratory infection Immunosuppression |
| Apremilast: Anti-phosphodiesterase-4 | 20 or 30 mg orally every day | 40% (week 16) (30 mg BID group) | 21% of PsA patients (week 16) 24% of Ps patients (30 mg BID) | Unknown | Nausea Diarrhea URI Immunosuppression |
There are limited data on the use of TNF-α inhibitors in the pediatric population, but etanercept is approved for the treatment of DMARD-resistant polyarticular JIA, and glucocorticoids, NSAIDs, or other analgesics may be continued during therapy. Recommended (off-label) dosages are 0.8 mg/kg (maximum: 50 mg/dose) once weekly or 0.4 mg/kg (maximum: 25 mg/dose) twice weekly. Infliximab is approved for children aged 4 years and older at doses of 3 mg/kg (weeks 0, 2, and 6), then 3 to 6 mg/kg/dose every 8 weeks thereafter. Infliximab has been used in children with JIA in combination with MTX. Similarly, data on adalimumab use in JIA is sparse, but the drug has been recommended for severe cases for children of at least 4 years in doses of 20 mg subcutaneously every other week (patient weight 15 kg to <30 kg), and 40 mg subcutaneously every other week for children weighing 30 kg and greater.
Newer anti–TNF-α agents include golimumab and certolizumab pegol, both of which are FDA-approved for the treatment of PsA. Neither is yet approved for psoriasis, although improvement of skin lesions has been observed in clinical trials on PsA.
Interestingly, certolizumab pegol lacks the Fc portion of the TNF-α antibody, and hypothetically may be less likely to induce antibody-related complement activation, apoptosis, or cellular toxicity. In a double-blind phase III trial on certolizumab pegol use in 368 patients with PsA (the RAPID-PsA trial), 20% of patients with PsA who had previously experienced inadequate responses to another TNF-α inhibitor demonstrated responses similar to those of the overall study population. ACR20 response was achieved in 58.0% and 51.9% of the 2 treatment arms (200 mg certolizumab once every 2 weeks or 400 mg once every 4 weeks) at week 12, independent of prior TNF-α inhibitor exposure. PsARC improved in 78% of treated patients, and sustained improvements were observed in psoriatic skin involvement, enthesitis, dactylitis, and nail disease. Both dosage intervals of certolizumab pegol also resulted in rapid improvements in dermatologic-specific, PsA-specific, and generic health-related QOL outcome measures : At week 24, clinically meaningful and statistically significant differences in fatigue, pain, QOL, and Dermatology Life Quality Index (DLQI) measures were observed in both certolizumab pegol treatment arms, irrespective of prior TNF-inhibitor exposure.
Head-to-head comparison studies of the TNF-α inhibitors have not been performed. Some investigators have suggested combination therapy (see later discussion) or switching from one biologic to another to improve clinical efficacy in PsA, although this has not been supported by clinical evidence. A 2012 meta-analysis performed an indirect comparison of PsARC and patient-reported outcomes for the available anti-TNF agents at that time (adalimumab, etanercept, golimumab, and infliximab). Data from 20 publications representing 7 PsA clinical trials were analyzed; the investigators and did not find any statistically significant differences between the TNF-α inhibitors, as the data compiled in Table 2 also suggest.
TNF-α inhibitors do have significant limitations; namely, a substantial number of patients may lose efficacy over time, likely related to development of antibodies against the biologic. Additional major prohibiting factors to the use TNF-α inhibitors include their expense and the inconvenience of intravenous or subcutaneous administration.
TNF-α inhibitors are contraindicated in patients with serious infections, those with a history of demyelinating diseases, those with New York Heart Association (NYHA) class I or II heart failure and an ejection fraction of less than 50%, and in patients with NYHA class III or class IV heart failure. Likewise, adverse effects of TNF-α inhibitors include an increased risk of bacterial, viral, invasive fungal, and mycobacterial infections (all patients require annual tuberculosis testing), the development of or worsening peripheral or central demyelinating disease, lymphomas and other malignancies, reactivation of hepatitis B, and exacerbation of congestive heart failure. A small number of cases of new-onset psoriasis in patients have been reported. The TNF-α inhibitors are pregnancy category B. Live vaccines are contraindicated in patients receiving the drugs. The risk of malignancy may be higher in children, and these agents are used very cautiously in JPsA.
Ustekinumab
Ustekinumab is the only available fully human G1κ monoclonal antibody that binds to the p40 subunit of IL-12 and IL-23; it was approved in the United States in 2013 for the treatment of PsA. Single-nucleotide polymorphisms in the IL-23 receptor and IL-12 genes have been found to increase susceptibility to PsA. IL-23 potently promotes IL-17 and Th17 activation, and enhances osteoclastogenesis and bone resorption in mouse models. Inhibition of IL-12 has been shown to dramatically reduce pathogenic IL-12–induced synovial tissue levels of TNF-α and IFN-γ.
In PsA, ustekinumab at a dose of 45 mg (if <100 kg; 90 mg if >100 kg) subcutaneously at weeks 0, 4, 12, then every 12 weeks thereafter leads to significant improvements in enthesitis, dactylitis, physical functioning, radiographic progression of disease, and patient QOL. Its long half-life allows for ongoing efficacy with a dosing interval of 12 weeks, giving it the longest dosing interval of all currently available medications for PsA. Of note, ustekinumab also has shown good efficacy in PsA patients who have previously received NSAIDs, DMARDs, and TNF-α inhibitors. Of consideration is the fact that in some markets the 90-mg dose is twice as expensive as the 45-mg dose. Ustekinumab fills an unmet need in PsA therapy; it is an option for nonresponders to TNF-α inhibitors and for patients in whom the TNF inhibitors are contraindicated, whether for prior adverse effects or comorbid conditions.
Most adverse effects associated with ustekinumab are mild and include nasopharyngitis, upper respiratory infections (URI), and headache. No opportunistic infections (including tuberculosis), malignancies, or deaths occurred in either of the large phase III PSUMMIT-1 or -2 trials. Although there has been particular concern regarding cardiovascular risks associated with anti–IL-12/23 agents, leading to the withdrawal of briakinumab from the market, a large 2013 postmarketing study reported that ustekinumab use for up to 5 years in patients with psoriasis did not lead to an increased risk of major adverse cardiovascular events (MACE). Similarly, the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study found comparably low rates of MACE with ustekinumab (0.21 events per patient-years of observation) as seen with adalimumab and etanercept.
Ustekinumab is FDA pregnancy category B. A theoretic increased risk for infection with Mycobacterium and Salmonella has been suggested, given reports of increased susceptibility to these infections of patients with IL-12 receptor deficiency.
Apremilast
Apremilast, a phosphodiesterase-4 inhibitor, is a recently FDA-approved, orally administered small molecule that has shown substantial efficacy in PsA and many other inflammatory arthritides. In the PALACE trials, apremilast (30 mg twice daily) led to an average ACR20 achievement at week 52 in 43%, 28%, and 32% of PsA patients who were biologic-naïve, biologic-experienced, and DMARD-naïve, respectively. Reductions in enthesitis and dactylitis, and improvements in QOL and physical functioning, were also statistically significant at week 52.
Apremilast is unique to the PsA market. It acts at an intracellular level, indirectly blocking TNF-α and other proinflammatory cytokines via inhibition of the cyclic adenosine monophosphate pathway. Adverse effects of apremilast include diarrhea and nausea, the incidence of which decreases with length of treatment time, URI, and headache (see Table 2 ). Effects of apremilast on radiographic progression of PsA and studies on its long-term efficacy are under way.
Emerging Therapies for Psoriatic Arthritis
IL-17 and other Th-17 cytokines play a crucial role in PsA pathogenesis, and therapies targeting this pathway (including IL-17A and the IL-17 receptor), secukinumab, brodalumab, and ixekizumab, are under investigation for the treatment of PsA. The IL-17 cytokine family consists of 6 cytokines (interleukins 17A to 17F) and 5 receptors (interleukins 17RA to 17RE), and overproduction of interleukins 17A, 17F, and 17A/F induces expression of proinflammatory cytokines with pathologic consequences, including the proliferation of keratinocytes in psoriasis. Levels of IL-17 are elevated in the lesional skin, serum, and synovial fluid of patients with psoriasis and PsA, and correlate with disease severity in psoriasis. In animal models of inflammatory arthritis, IL-17 neutralization reduces arthritis severity by diminishing joint inflammation and inhibiting structural damage.
Each of the IL-17 agents currently under investigation is administered subcutaneously at varying intervals ( Table 3 ). Secukinumab is a fully human monoclonal immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to and neutralizes IL-17A, with demonstrated success in trials for moderate-to-severe plaque psoriasis, PsA, RA, and AS. In a phase II randomized clinical trial in 42 patients with active PsA, ACR20 was reached by 43% of patients receiving secukinumab at week 24 (see Table 3 ). Patient-reported outcomes of health-related disability and QOL also showed improvements, and further study of the drug in larger patient populations is under way. Adverse events in the study were comparable with those observed in patients receiving placebo. Further study of secukinumab in larger patient populations is needed, as the drug has shown remarkable efficacy in cutaneous psoriasis in phase III studies. In a head-to-head comparison study of secukinumab to etanercept in plaque psoriasis, secukinumab (in both 150-mg and 300-mg doses) showed improved efficacy to etanercept throughout the 52-week study period.
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