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10 Articles in Volume 17, Issue #6
A Plea for Proper Opioid Tapering
Centers of Excellence in Pain Management: Past, Present, and Future Trends
Comorbid Pain and Childhood Obesity
Discussing Migraine With Your Patients: A Common Sense Guide for Clinicians
Justification of Morphine Equivalent Opioid Dosage Above 90 mg
Letters to the Editor: Dependence vs Addiction, Opioid Metabolism
Opioid Rotation From Opana ER Following FDA Call for Removal
Psoriatic Arthritis: Established, Newer, and Emerging Therapies
Sleep-Wake Disorders and Chronic Pain: Reciprocal and Interactive Effects
What are Nav1.7 inhibitors and how are they used in the treatment of neuropathic pain?

Psoriatic Arthritis: Established, Newer, and Emerging Therapies

A look at the mechanisms and pathophysiology that appear as contributing factors to musculoskeletal inflammation, bone irregularities, and resultant symptoms seen in this form of arthropathy.

Psoriatic arthritis (PsA) is a type of spondyloarthritis that develops in up to 30% of patients who have psoriasis; it has an estimated prevalence between 30 and 100 cases per 10,000 people in the United States.1 The incidence of PsA is similar among men and women, and it occurs less commonly among Asian and black individuals. Although PsA generally presents about 10 years after an initial psoriasis diagnosis, the order in which symptoms of the disease manifest can vary, and multiple symptoms may occur simultaneously.

 

Clinical features of PsA may present in 6 clinical domains that direct diagnosis and treatment—peripheral disease, axial disease, enthesitis, dactylitis, skin disease, and nail disease.1 Pain and stiffness commonly occur in peripheral and/or axial joints. Enthesitis, or swelling at the insertion site of tendons or ligaments to bone, typically is seen at the Achilles tendon or plantar fascia. Dactylitis, or pain and inflammation of the toes and fingers, can be acute or chronic. Up to 50% of patients with PsA have enthesitis and dactylitis. Axial involvement of the spine and sacroiliac joint also is common.2 Nail dystrophy causing onycholysis, pitting, or hyperkeratosis is observed in a majority of patients. Patients with PsA also may be at a higher risk for cardiovascular events, type 2 diabetes, fatty liver, hypertension, and metabolic syndrome.

The spectrum of arthropathy symptoms can vary from arthritis in distal interphalangeal joints to arthritis mutilans, a highly destructive arthritis subtype that often causes shortening and malformation of the digits.

Pathophysiology and Etiology

Since not all patients with psoriasis develop PsA, several mechanisms are believed to contribute to the musculoskeletal inflammation, bone abnormalities, and resultant symptoms of PsA.1,3 In psoriasis, the effect on the skin occurs as a result of type 1 and type 17 helper T-cell (TH1 and TH17) pathways triggering release of various inflammatory substances, such as interleukin (IL)-23, IL-17, and tumor necrosis factor (TNF). These inflammatory substances induce migration of monocytes and T cells in response to local stress to a joint, resulting in synovial inflammation.

Proposed factors that put stress on joints include infection, trauma, and autoimmune reactions. The presence of interferon γ, TNFα, and various TH17 cytokines have been found during laboratory analysis of synovial fluid of patients with PsA.2 In addition to autoimmune and inflammatory markers, a high concentration of osteoclastic precursors and upregulation of receptor activator of nuclear factor κβ ligand has been detected in the synovial lining of affected patients.

The likelihood of a patient with psoriasis developing PsA increases with psoriasis severity.1,3 The risk of developing PsA also is higher in patients with a family history of PsA. Genetic alterations and the presence of certain human leukocyte antigens (HLA), such as HLA-B27, as well as major histocompatibility complex alleles, have been linked to PsA. Other factors that may increase the risk of PsA include infection, obesity, trauma, and inflammatory bowel disease.

Diagnosis

Clinicians caring for patients with psoriasis should routinely inquire about symptoms of painful joints, morning stiffness, and changes in the appearance of joints.1 The Classification Criteria for Psoriatic Arthritis (CASPAR), although not validated as diagnostic criteria, can guide clinicians in the identification of PsA in patients who present with inflammatory musculoskeletal disease of joints, the spine, or entheses.

The following criteria are used for classification:

  • Evidence of current psoriasis or a personal or family history of psoriasis
  • Nail dystrophy
  • Current or past dactylitis
  • Radiographic evidence of new bone formation
  • Negative rheumatoid factor

When present, each of these components is given a single point, except for current psoriasis (rather than personal or family history), which is assigned 2 points. A score of at least 3 points on the CASPAR classification indicates the presence of PsA. The CASPAR classification also has been used to form inclusion criteria for enrollment into clinical trials evaluating PsA treatments.

Conditions that should be ruled out before establishing a diagnosis of PsA include:

  • Gout
  • Rheumatoid arthritis (RA)
  • Ankylosing spondylitis

Laboratory measurements and imaging studies can aid in establishing a correct diagnosis. Rheumatoid factor and anti-cyclic citrullinated peptide antibodies typically are negative in patients with PsA.1,2 General markers of inflammation, such as serum C-reactive protein and erythrocyte sedimentation rate, are elevated in about 40% of patients with PsA, and 25% of patients are positive for HLA-B27. Typical findings on imaging studies include bone and cartilage destruction along with new bone formation. Patients with a poor prognosis are those with multiple affected joints and elevated inflammatory markers.4

Pharmacologic Treatment

The goals of therapy in PsA are to achieve remission and low or minimal disease activity, optimize functional status, prevent structural joint damage, and minimize complications of active disease and its treatment.

Treatment decisions should consider the presentation of disease activity in each of the 6 clinical domains of PsA. The presentation may be heterogeneous among these domains, and the domain with the most severe symptoms should direct the choice of treatment.

The most widely followed current guidelines on the treatment of PsA are those authored by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the European League Against Rheumatism (EULAR), which offer differing recommendations.4,5

The 2015 GRAPPA guideline committee formed focus groups that reviewed literature and provided treatment recommendations for each of the clinical domains of PsA and for comorbidities.4 The 2015 EULAR guideline, in contrast, provides an algorithmic approach to attain remission through various treatment phases based on disease severity and prior treatment responses (phases I through IV).5 Although the EULAR guideline does not organize recommendations by clinical domain or comorbidity, it does provide some recommendations for specific clinical domains that generally coincide with those from the GRAPPA guideline.

Both guidelines describe the use of established therapies (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], corticosteroids, disease-modifying antirheumatic drugs [DMARDs]) and emerging therapies, including agents approved for other indications. Table 1 lists the US Food and Drug Administration (FDA)-approved drugs for PsA, as well as dosing considerations, and describes where these drugs fit into the guidelines.1,4-8 Generally, an adequate trial of a particular agent, given that the treatment is tolerated, is between 3 and 4 months in duration.9,10

Established Therapies NSAIDs and Corticosteroids

Generally, mild disease with oligoarticular involvement, axial disease, and enthesitis are treated with NSAIDs.1,4,5 The NSAIDs are recommended for improvement of musculo-skeletal signs and symptoms but carry risks that should be considered on a patient-specific basis. These include gastrointestinal bleeding, worsening renal function, hypertension, adverse cardiovascular events such as myocardial infarction and stroke, and, rarely, severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome.11

Response to NSAID therapy can be anticipated within several weeks, and treatment should be modified if a response is not achieved by 3 months. Some researchers have defined an adequate trial as at least 2 different NSAIDs at maximum tolerated dosages for 2 weeks each.

In addition, adjunctive corticosteroid therapy, administered systemically or via local injection, may be considered.1,4,5 Intra-articular corticosteroids may be particularly beneficial in patients with mono- or oligoarthritis, dactylitis, and enthesitis, although GRAPPA recommendations on this use are not strong. Corticosteroid therapy should be administered at the lowest dosage and shortest duration possible to minimize common adverse events, such as hemodynamic, immunologic, metabolic, and psychological effects, as well as withdrawal-associated psoriasis flare.4,12

DMARDs

The goal of preventing structural joint damage can be achieved with the use of conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs in patients with peripheral arthritis.1,4,5 Early introduction of therapy with these agents (ie, within 3 months of active peripheral PsA) may provide additional benefit in patients who are more likely to experience progressive joint damage, such as those with a larger number of inflamed joints, elevated inflammatory markers, or extra-articular disease.

Conventional Synthetic DMARDs

Among the conventional DMARDs, methotrexate (MTX) generally is preferred, despite a lack of conclusive effect on radiographic progression, because of its long history of use and greater effects on skin involvement than other conventional DMARDs. Notably, the GRAPPA guideline does not recommend conventional DMARDs for the treatment of axial disease or enthesitis because of a lack of efficacy in these domains.4

Biologic DMARDs

Biologic agents have the greatest amount of clinical data supporting their efficacy in inhibiting the progression of structural damage, and the prescribing information for some products contain FDA-approved claims to this effect (see Table 1).1 However, all biologic agents have demonstrated at least mild efficacy in structural modification of joints. Patients with peripheral arthritis who have an inadequate response to initial NSAID or corticosteroid therapy can receive conventional or biologic DMARDs, depending on the severity of the other PsA clinical domains.4,10

Biologic DMARDs are included within the treatment algorithms of all PsA clinical domains, either as a first-line treatment or for a disease that is resistant or intolerant to NSAIDs or conventional DMARDs. Although combination therapy of conventional with biologic DMARDs is not supported by enough evidence, there are some data suggesting a prolongation of time to reduced response to infliximab when it is used with MTX.4,10

Classes of biologic DMARDs include TNF inhibitors and the newer IL-17 and IL-12/23 monoclonal antibodies (MABs). The TNF inhibitors generally are preferred as first-line biologic DMARDs. These agents have demonstrated comparable efficacy in PsA outcomes, including at least mild structural improvement of joint disease and, thus, the choice of a TNF inhibitor generally is driven by dosing frequency, route of administration, cost, and payer requirements.1 The decision also may be influenced by new-to-market biosimilar products for agents such as adalimumab (Humira, biosimilar Amjevita), etanercept (Enbrel, biosimilar Erelzi), and infliximab (Remicade, biosimilar Inflectra).6,10 Patients who fail to respond or are intolerant to a TNF inhibitor may switch to other agents in the class or to another class of DMARD therapy.4,5

Prior to use of biologic DMARDs, screening for latent tuberculosis, HIV, and hepatitis B and C infection is recommended, and appropriate therapy should be initiated when the result is positive.4 Patients treated with any biologic DMARD should be monitored for adverse events, including an increased risk of infections, injection site reactions, and a reduced response to vaccination.

Newer Therapies

IL MABs

Improvement in joint symptoms, radiographic outcomes, and skin manifestations also has been seen with the newer biologic DMARDs approved for PsA—the IL-12/23 MAB ustekinumab (Stelara) and the IL-17 MAB secukinumab (Cosentyx).1,10 Evidence of ustekinumab’s efficacy is based on placebo-controlled trials in patients with PsA resistant to NSAID or DMARD treatment, in which it showed significant improvements in joint and skin disease.13 Secukinumab demonstrated significant improvement over placebo in skin disease and physical functioning in patients who failed other PsA treatments in 2 large Phase III trials.13 Another IL17 MAB, brodalumab, also was evaluated for treatment of PsA; however, due to concerns of increased suicidal ideation, all trials of this agent were halted in May 2015.13 The approved IL MABs for PsA is recommended for patients with peripheral arthritis who have failed a conventional DMARD and are not candidates for TNF inhibitors.5 Long-term safety data of this newer class of agents will further delineate their place in PsA therapy.

Phosphodiesterase-4 inhibitor

The phosphodiesterase-4 inhibitor apremilast (Otezla) is a new oral targeted synthetic DMARD that is FDA approved for the treatment of psoriasis and PsA.1 It has shown similar efficacy to MTX with respect to skin outcomes but a lower response to arthritis outcomes compared to biologic DMARDs. According to the GRAPPA guideline, apremilast can be used for peripheral arthritis that is conventional DMARD-resistant, with the caveat that data on reduction or prevention of joint damage are not available.4 According to EULAR recommendations, its place in therapy is for patients with peripheral arthritis that is conventional DMARD-resistant and in whom a biologic DMARD may not be appropriate.5 Evidence for the efficacy of apremilast in other PsA clinical domains is emerging.4 Apremilast generally is fairly well tolerated, with mild adverse events of diarrhea and nausea.10 However, concerns of unexplained weight loss and depression require further investigation.

Emerging Therapies

Ixekizumab (Taltz), an IL-17 MAB that is FDA approved for plaque psoriasis, is being evaluated in Phase III trials of patients with PsA who are biologic DMARD-naïve and who have treatment-resistant disease.14,15Preliminary results showed significant improvement in disease activity with ixekizumab compared to placebo in both trials. However, it is unclear when the manufacturer may submit an application for FDA approval of ixekizumab in PsA.16

Tofacitinib (Xeljanz), an oral agent, is a janus kinase inhibitor that interferes with T-cell activation.13 Its approved use is for DMARD-resistant RA. Phase III trials comparing its efficacy to placebo in PsA recently have shown significant improvements with tofacitinib in American College of Rheumatology 20 (ACR20) response in both TNF-naïve and TNF-experienced patients.15-20 The manufacturer has submitted an application for FDA approval of tofacitinib in PsA, with a decision anticipated in late 2017.21

Another agent with potential efficacy in PsA is a recombinant human fusion protein, abatacept (Orencia).13 This biologic, approved for use in RA, blocks an area on antigen-presenting cells that prevents the co-stimulation of T-cell activity. A Phase III trial found significant improvements with abatacept compared with placebo in ACR20 response in patients with an inadequate response or intolerance to 1 or more conventional DMARDs.22Based on these data, the manufacturer has submitted an application for FDA approval of abatacept in PsA, although no timeframe for FDA action has been specified.23

Compounds with unique mechanisms, as well as some agents indicated for other conditions, such as cancer, also have shown promise in PsA.13 Preclinical development of nerve growth factor inhibitors (K252a) and mechanistic target of rapamycin inhibitors (NVP-BEZ235 and Kv1.3) continues as an understanding of the pathogenesis of PsA deepens. The potential of vascular endothelial growth factor inhibitors, such as bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nexavar) in PsA also has been suggested in case reports.13

Other Interventions

In addition to pharmacological treatment, patients with PsA can benefit from physical and occupational therapy as well as regular exercise.10 Maintenance of a healthy weight can improve response to DMARD therapy and positively impact common comorbidities, such as obesity, type 2 diabetes, cardiovascular disease, and metabolic syndrome.4,10 Patients with PsA should be screened not only for these conditions but for osteoporosis, fatty liver disease, depression, anxiety, inflammatory bowel disease, and ophthalmic disease.4 These conditions are more common in patients with PsA than in the general population, and these comorbidities can impact the choice of PsA treatment (see Table 1).

Conclusion

Patients with PsA require a thorough evaluation of symptoms in all applicable clinical domains and comorbidities to establish an appropriate treatment. The use of NSAIDs and/or corticosteroids is indicated for the management of musculoskeletal symptoms. Early introduction of DMARD therapy is recommended in patients with more severe PsA. MTX is the preferred conventional DMARD because of its benefit in joint and skin manifestations.

Biologic DMARDs have the most data supporting their efficacy in preventing disease progression, and when their use is indicated, TNF inhibitors are first-line agents. Data on long-term safety and efficacy of newer agents approved in PsA, including IL MABs and apremilast, will help further delineate their place in therapy. Preliminary results of ongoing clinical trials evaluating the efficacy of abatacept, ixekizumab, and tofacitinib, and development of novel agents with unique mechanisms show promise in expanding future PsA treatment options.

Last updated on: August 16, 2017
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