- Does this patient have psoriatic arthritis?
- What tests to perform?
- How should patients with psoriatic arthritis be managed?
- What happens to patients with psoriatic arthritis?
How to utilize team care?
Are there clinical practice guidelines to inform decision making?
What is the evidence?
Does this patient have psoriatic arthritis?
Psoriatic arthritis (PsA) is an inflammatory arthritis that is characterized by a diversity of clinical manifestations and a highly variable disease course. This disorder was not recognized as a discrete entity until 1964, and it was Moll & Wright’s landmark paper in 1973 that outlined the cardinal clinical features followed by familial studies a year later that documented the contribution of genetic factors in disease etiology.
Innovative translational studies and clinical trials over the last fifteen years have uncovered new disease mechanisms and fostered the development and validation of novel therapies, which have been incredibly effective for the varied clinical features of this disease. Recent attention has focused on the extra-articular manifestations and comorbid conditions associated with PsA because they may lessen function and quality of life and increase mortality.
In the assessment of a patient for possible PsA, it is important to focus on the history and physical examination of the five key domains of this disease, which include integument manifestations of psoriasis, inflammatory peripheral arthritis, spondylitis, enthesitis, and dactylitis.
Several forms of psoriasis can be associated with arthritis, including vulgaris, guttate (drop-like), pustular, flexural (groin, anal folds, and other flexural areas), and erythroderma. The most common form is psoriasis vulgaris and, on average, the psoriasis precedes the arthritis by ten years; however, in 15% of patients, the skin and joints manifest concurrently and, in another 15%, joint symptoms precede the onset of psoriasis. A small subset with arthritic features (clinical and radiographic) but no skin involvement, labeled "sine psoriasis," has also been described. It is estimated that approximately 25% of psoriasis patients develop arthritis.
Patients with more severe psoriasis are more likely to have arthritis, but the correlation between severity of skin and joint disease in an individual patient is quite low. Nail lesions are observed in a high proportion of PsA patients and take on many forms (pits, onycholysis, ridges, and erosions). It is important to note that psoriasis can profoundly affect the mood and psyche, so monitoring for symptoms and signs of depression and social withdrawal are an essential component of high quality care in this population.
Three patterns of joint involvement - oligoarticular, polyarticular, and isolated distal interphalangeal joint (DIP) inflammation - have been observed in PsA. Patients present with joint pain, stiffness, and redness, but joints are less tender in comparison to rheumatoid arthritis (RA). At times, intense purplish discoloration over the joint is observed, and distal limb edema has also been reported. PsA distribution is quite unique in that involvement of individual rays of the hand or feet may differ markedly with juxtaposed (in one digit) or alternating (between digits) areas of excessive bone resorption and new bone formation.
As a rule, polyarticular disease and erosions are markers for disease progression. A widely quoted study of an early PsA cohort with peripheral arthritis reported that approximately half the patients manifested erosions after 2 years and the majority were on disease-modifying anti-rheumatic agents (DMARDs) at this time point. Arthritis mutilans, a rare form of PsA, marked by excessive bone resorption with digits that are telescoped and flail, has been observed much less commonly over the last decade for unknown reasons. Isolated DIP disease is rare and often associated with marked nail inflammation.
The prevalence of axial involvement in PsA varies according to the series and inclusion criteria, but estimates of 24-50% in the lower spine and sacroiliac (SI) joints have been reported, and the prevalence of cervical disease may be even higher, with estimates closer to 60% based on radiologic criteria. In a recent study, the impact of spondylitis on pain and function in PsA was similar in magnitude to ankylosing spondylitis although it is more likely to be unilateral in PsA. In addition, gastrointestinal (GI) inflammation is less commonly observed in psoriatic spondylitis compared to AS. Measures used to assess AS (BASDAI, Shober score, chest expansion, occiput to wall distance and lateral flexion) can be used in the evaluation and longitudinal monitoring of PsA patients with spinal involvement. Isolated spinal disease can occur but is very uncommon in PsA, and differentiation from axial spondyloarthritis (ankylosing spondylitis, non-radiographic axial spondyloarthritis) may not be possible, particularly if the arthritis precedes onset of the skin disease.
Enthesitis, or inflammation at insertion sites of tendons, ligaments, and joint capsules onto bone is a central element of the spondyloarthropathies. Common sites of involvement include the plantar fasciae, patellar and quadriceps and Achilles tendons, and insertion sites in the iliac crest and the rotator cuff. Patients present with localized pain and, occasionally swelling at the insertion or more widespread discomfort that must be differentiated from fibromyalgia or other chronic pain syndromes.
Subclinical enthesitis (detected by ultrasound) is quite common in psoriasis patients although isolated enthesitis as a clinical feature is not common in PsA. Examination of enthesial sites can be performed rapidly in the clinic and should be part of the musculoskeletal examination in all patients with psoriasis and possible psoriatic arthritis.
Diffuse swelling of a ray or ‘sausage digit’ is considered a characteristic finding in PsA, although it can also be observed in other forms of spondyloarthritis, sarcoidosis, gout, sickle cell disease, and tendon sheath infections. In PsA, inflammation can be acute (tender) or chronic (non-tender); both forms have been associated with joint erosions and new bone formation. Imaging findings on magnetic resonance imaging (MRI) revealed circumferential soft tissue edema, synovitis, flexor tenosynovitis, and a spectrum of bone edema. The primary difference in MRI findings between tender and non-tender dactylitis was bone edema. Dactylitis is considered a marker of severity because it is associated with polyarticular disease and bone erosions.
Up to 10% of patients with PsA develop uveitis, which is seen most frequently in males who are HLA-B27 positive. The eye inflammation is distinct from that observed in ankylosing spondylitis because it is more often bilateral, insidious in onset, can involve the posterior pole of the eye, and often requires NSAIDs or additional immunosuppressive therapy to control pain related to continuous inflammation. The limited studies performed to date suggest that axial disease, uveitis, and colitis cluster together in PsA patients, perhaps linked by an HLA-B27-dependent mechanism, but further studies are required.
Psoriasis and PsA patients also have a significantly higher rate of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome than age-matched controls. In addition, hypertension, hyperlipidemia and cardiovascular disease, including myocardial infarction are more common in patients with psoriasis and PsA than controls. A number of studies have demonstrated increased intimal thickening in the carotid arteries in PsA subjects compared to controls even in patients with low to moderately elevated Framingham Risk Scores. Aggressive risk-factor modification and suppression of inflammation might lessen the frequency and severity of these comorbidities.
The most important elements to glean from the history are symptoms of inflammatory peripheral arthritis presenting as morning stiffness, joint pain and/or swelling, and difficulty in performing daily activities. Patients often complain of inflammatory back or neck pain that is most notable in the morning and improves with exercise and non-steroidal inflammatory medications. The pain is often most troublesome in the middle of the night. The majority of patients have psoriasis that can range from mild to severe and may be difficult to identify on exam. It is important to inquire about scalp and inverse psoriasis (groin, axilla, naval) and skin lesions beneath the breasts.
Some patients may not have psoriasis but will recall a family history of psoriasis or psoriatic arthritis, which is important to document. Other important elements in the history are symptoms of enthesitis (pain and/or swelling at insertion of tendons, ligaments, or joint capsules into bone [plantar fascia, Achilles tendons, patellar and quadriceps tendon insertions, lateral and medial epicondyles] and dactylitis (diffuse swelling with or without tenderness in a finger or toe).
In the physical exam, a careful examination of the skin in search for psoriatic plaques is essential. The plaques may be difficult to see in patients with scalp, inverse or palmar, plantar involvement. In addition, close attention to the body mass index (BMI), blood pressure and signs of elevated cholesterol and diabetes can identify important metabolic features. The musculoskeletal exam should be complete with examination of peripheral joints, including the feet and DIP joints, entheses, digits in search of dactylitis and nail changes of psoriasis (pitting, onycholysis), and involvement of the axial skeleton (Shober score, occiput-to-wall, neck range of motion, and lateral bending). It is also important to examine gait and station.
Psoriasis mimics include eczema, cutaneous T cell lymphoma, seborrheic dermatitis, tinea corporis and cruris, discoid and subacute lupus and lichen planus. A skin biopsy should be strongly considered, particularly in patients with atypical clinical phenotypes. The differential diagnosis of psoriatic arthritis is rheumatoid arthritis, reactive arthritis, ankylosing spondylitis, axial spondyloarthritis, enteropathic arthritis, SLE, and osteoarthritis. Fibromyalgia can also mimic enthesitis and can co-occur with PsA.
What tests to perform?
The most important role of lab testing is to exclude other considerations in the differential diagnosis. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and antinuclear antibodies (ANA) may be helpful in some patients if there are symptoms that suggest a diagnosis of RA or systemic lupus erythematosus (SLE). However, some patients with psoriatic arthritis alone may have positive tests. Acute phase reactants (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) may provide insights into disease activity, although many patients with active PsA have normal acute phase reactants.
It is also important to check a comprehensive metabolic and lipid profile since obesity, metabolic syndrome, type 2 diabetes, fatty liver, and hyperlipidemia are very common features in PsA and the presence of these conditions will influence treatment considerations. In patients who are under consideration for a DMARD, such as methotrexate of leflunomide, it is recommended to check hepatitis B and C serologies and baseline transaminases; testing for exposure to tuberculosis should be done if a biologic, such as an anti-TNF agent, is anticipated. An increased rate of progressive liver fibrosis based on serial biopsies was reported in psoriasis patients with obesity or type II diabetes treated with methotrexate. It is also critical to ensure that women of child-bearing age are not pregnant so a pregnancy test may be required.
The heterogeneity of clinical features in PsA can provide unique challenges to the clinician. Fortunately, a number of imaging modalities can assist in diagnosis, management, and assessment of treatment response. Imaging studies also play an increasing role in the analysis of disease mechanisms (enthesitis, dactylitis, new bone formation) as well.
Initial evaluation of patients with new onset inflammatory arthritis and psoriasis include plain radiographs of involved joints. It is important to image the anterior-posterior (AP) pelvis, with additional views of the spine if symptoms are present in the neck, thorax or low back.
Musculoskeletal ultrasound has rapidly emerged as an important imaging modality in PsA because it can visualize entheseal and synovial inflammation along with early erosions.
MRI studies reveal bone marrow edema, an important finding in PsA along with entheseal and synovial inflammation, and can also detect erosions. Scintigraphy can assist in the evaluation of joint pain or entheseal pain in psoriasis patients with no findings on joint exam. It must be emphasized, however, that many psoriasis patients have subclinical findings on imaging studies, although the significance of these abnormalities is not well understood.
Fatty liver is commonly observed in patients with an elevated BMI and a fibroscan may be considered to evaluate for fibrosis and cirrhosis in patients with persistently elevated liver function tests.
Skin biopsy is sometimes required to confirm a diagnosis of psoriasis to differentiate from eczema, subacute cutaneous lupus, cutaneous lymphoma, or syphilis.
Controversies in diagnostic testing
Occasionally, patients with PsA will have a positive rheumatoid factor and/or anti-CCP antibody. The main differential diagnosis in this setting is psoriasis with RA or PsA with a serologic antibody that is not clinically significant. Generally, a careful physical exam and careful review of the X-rays will help the clinician decide between these two possibilities
How should patients with psoriatic arthritis be managed?
The articular and dermatologic manifestations associated with PsA are remarkably heterogeneous in both the extent and type of tissue involvement. Patients with PsA, a chronic systemic inflammatory disorder, may develop not only peripheral arthritis but also axial disease, dactylitis, enthesitis, and skin and nail psoriasis, with consequent adverse impact on function and quality of life (QOL).
Heterogeneity is observed not only in disease manifestations but also in severity and course, which can vary from very mild psoriasis or enthesitis to widespread psoriatic plaques, disfiguring nail disease, and severe joint inflammation with destruction that can result in disability and increased mortality. Moreover, comorbidities associated with psoriasis, such as the metabolic syndrome, can contribute to damage in multiple end-organs and often leads to markedly impaired QOL as well as early mortality.
Management of patients with psoriatic arthritis
Comprehensive management of psoriatic arthritis should be centered on treatment of the key elements of the skin and joint disease coupled with management of the comorbidities with regimens that are simple and safe. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) published treatment recommendations (see below) that address the 5 key domains: skin disease and nail disease, peripheral arthritis, spondylitis, enthesitis, and dactylitis. Treatment recommendations that focus on the musculoskeletal features of PsA were also published by EUropean League Against Rheumatism (EULAR).
The role of DMARDs in PsA has not been well defined. Few high quality clinical trials have been published and, thus, many decisions regarding the use of these drugs are not grounded on strong evidence. Methotrexate is commonly prescribed in PsA based on its efficacy in rheumatoid arthritis and proven value in psoriasis. However, in the Methotrexate in Psoriasis trial (MIPA), methotrexate was not more effective than placebo for peripheral arthritis, although the maximum dose was only 15 mg per week and the study may have lacked sufficient power. A phase III trial comparing methotrexate with etanercept and entanercept plus methotrexate is currently in progress; the results of this study will clarify the efficacy and safety of methotrexate in this disease.
Moreover, an effect of this drug on enthesitis and dactylitis or inhibition of X-ray progression has not been established. In the recent Tight Control of Psoriatic Arthritis (TICOPA) trial, over 50% of patients achieved minimal disease activity on methotrexate or a combination of DMARDs at 2 years. Interestingly, the tight control group did not show differences in x-ray progression compared to those who received usual care. These data provide the first insights into the possible efficacy of DMARDs in an early disease cohort. Leflunomide showed efficacy for peripheral arthritis in a phase 2b trial but is not effective for psoriasis. Well-designed studies analyzing the efficacy of Azulfidine revealed a small effect size in PsA.
The anti-TNF agents (adalimumab, certolizumab, etanercept, golimumab, and infliximab) have gained wide acceptance in psoriatic arthritis because they have shown efficacy for symptoms and signs of psoriasis and arthritis, and they inhibit X-ray progression in this disease. Most importantly, they are effective for all domains of disease including psoriasis, peripheral arthritis, axial disease, dactylitis and enthesitis. They are reasonably well tolerated, although the high cost remains a major barrier for many patients. Paradoxically, some patients develop psoriasis, alupus like reaction, uveitis, sarcoidosis or Crohn’s disease on anti-TNF agents. The lupus presentation often involves a photosensitive rash and arthralgias and major organ involvement is not common although antibodies to double stranded DNA may occur. The psoriasiform lesions are typically palmopustular but may appear as typical psoriatic plaques. The palmopustular variant is often difficult to treat and may require occlusive dressings. Sometimes a switch to another anti-TNF agent is associated with resolution of the adverse event but in some patients switch to a therapy in a different class is required.
The pathogenesis of these unusual phenotypes is poorly understood although a skewing towards production of type I inferons precipitated by TNF blockade has been proposed. An oral agent, apremilast was recently approved for PsA. This agent has an excellent safety profile and is also effective for psoriasis. Observed side effects include headache, abdominal pain and diarrhea, weight loss and depression with reports of suicidal ideation. Ustekinumab, the anti-P40 antibody that binds to IL-12 and IL-23, was approved for PsA and is now an option for patients who cannot tolerate or do not respond to anti-TNF agents. Ustekinumab is also effective for enthesitis and dactylitis, and does slow radiographic progression. A phase III trial of ustekinumab in ankylosing spondylitis was discontinued for lack of efficacy so this agent may not be ideal for patients with psoriatic spondylitis. Secukinumab is also approved for psoriasis and psoriatic arthritis. This agent is an IL-17A antagonist that is effective for dactylitis and enthesitis and also inhibits radiographic progression.
Secukinumab is also approved for ankylosing spondylitis and provides another option for patients with axial manifestations of PsA. Ixekizumab, another anti-IL-17A antibody is approved for treatment of psoriasis and demonstrated similar efficacy in PsA as secukinumab although it did not achieve enthesitis endpoints in either of the phase III trials. This agent was quite effective for patients who were inadequate responders to DMARDs or anti-TNF agents. Guselkumab, an anti-IL-23 antibody was recently approved for treatment of psoriasis and data from a phase II randomized trial in PsA showed good efficacy and safety. Lastly, tofacitanib, a Jak-STAT inhibitor showed strong efficacy and safety for PsA patients refractory to DMARDs or anti-TNF agents but is not yet approved by the Food and Drug Administration.
For a patient with new onset of psoriatic arthritis, a key branch point in the decision process is the presence or absence of erosions or joint space narrowing. If joint damage is present, it is common practice to start an anti-TNF agent. If not, apremilast, methotrexate or leflunomide is an option, although it is very important to avoid use of this agents in patients who are obese and have type II diabetes or steatosis because of the risk of progressive liver disease. Likewise, it should be avoided in patients who consume alcohol on a regular basis. Leflunomide can also be effective for arthritis but it is not effective for psoriasis.
If a patient without erosions does not respond to apremilast, methotrexate or leflunomide, it is common practice to add an anti-TNF agent, and, frequently, methotrexate (MTX) is discontinued if a patient responds to the anti-TNF drug, except in the case of infliximab where a low dose of MTX (7.5 mg per week) may lessen the development of drug-neutralizing antibodies. It is common practice to switch to a second, or even a third, anti-TNF agent for primary or secondary non-responders to a first anti-TNF molecule. It is not established if agents that block IL-12/23, IL-17 or Jak-STAT should be considered for early treatment of PsA since we do not have head-to-head data at this time.
Another approach for patients who fail an anti-TNF is to add or switch a DMARD, although the combination of anti-TNF agents and DMARDs has not been formally evaluated in this disease. For patients who cannot take or are non-responders to anti-TNF agents, apremilast, ustekinumab, or secukinumab are effective alternatives approved for treatment of PsA.
What happens to patients with psoriatic arthritis?
Genes implicated in the pathogenesis of PsA include Cw6,IL-23 R alleles and Act1, a molecule in the IL-17R signaling pathway and other MHC Class I alleles (B8, B27), Class I major histocompatibility complex chain-related gene A (MICA). Environmental events have also been associated with the onset of psoriatic arthritis, including rubella vaccination, injury sufficient to require a medical consultation, recurrent oral ulcers, moving house and fracture requiring hospitalization.
From a clinical perspective, PsA patients can present with features of RA (synovitis of the peripheral joints with erosions) or spondyloarthritis (enthesitis, osteitis, erosions, and new bone formation). The synovial pathology is more akin to findings in spondyloarthritis (SpA) than RA with infiltrating neutrophils, CD163+ macrophages, and the lack of an antibody response to the shared epitope as observed in RA.The importance of local biomechanical properties in disease pathogenesis, particularly as it relates to the enthesis, has been emphasized. The model of the synovio-entheseal complex delineates an innate immune response triggered by biomechanical and inflammatory events at the enthesis, which subsequently involve adjacent synovium and cartilage.
Altered bone remodeling is a cardinal finding in PsA, and studies have revealed increased levels of circulating osteoclast precursors migrating to the bone-pannus junction where receptor activator of NFkB ligand (RANKL) is expressed at high levels by synovial lining cells. SpA biopsy specimens and studies on peripheral blood support a potential role for bone morphogenetic proteins (BMP) and possibly molecules, which influence formation of osteoid via the Wnt signaling pathway (DKK-1, sclerostin) in pathologic new bone formation.
About 25% of psoriasis patients develop psoriatic arthritis. On average, patients develop psoriasis about ten years before arthritis although 15% of patients develop arthritis before psoriasis. Risk factors for arthritis are severity of psoriasis, obesity, nail disease, scalp disease, and a family history of psoriatic arthritis. Remission is rare in PsA, even on biologics based on older reports, but treatment of early disease may be associated with higher rates of remission based on recent studies that have not been published.
Mortality rates for PsA were higher than age-matched controls but recent evidence indicates that mortality may not be higher than observed in the general population. PsA patients do have higher rates of mortality from cardiovascular disease than controls.
Patients with psoriasis and PsA are frequently on multiple medications. They are often taking topical agents for psoriasis and either oral meds or injectable agents for psoriasis and PsA. Add to this the high prevalence of comorbidities (metabolic syndrome, cardiovascular disease, obesity) and the list of medications can become formidable. Thus, it is essential to simplify the treatment regimen as much as possible to maintain compliance. Obesity has also been associated with a reduced response to anti-TNF so patients with obesity and severe psoriasis and/or psoriatic arthritis may respond better to a drug that is administered using a weight based regimen (infliximab) or that targets other molecules.
How to utilize team care?
Specialty consultations include dermatology, orthopedics, podiatry, endocrinology, and cardiology.
Dermatology nurses with expertise in wound care.
Pharmacists are required for preparation of infusables.
Dieticians are key members of the team because of the high prevalence of obesity and metabolic syndrome.
Physical and occupational therapists and pedorthists are integral members of the team.
Are there clinical practice guidelines to inform decision making?
GRAPPA guidelines were published in 2016 and EULAR guidelines in 2015 (for details, see bibliography). The GRAPPA guidelines were recently updated; they provide a strategy for development of a treatment plan for individual patients that takes into account the five treatment domains outlined above. The EULAR guidelines focus almost exclusively on peripheral and axial arthritis.
Patients with psoriasis arthritis are rarely admitted to the hospital. Occasionally, they may develop erythroderma during steroid tapers or infection but this is not common. Duration of hospital admissions are highly variable.
What is the evidence?
Rahimi, H, Ritchlin, CT. "Altered bone biology in psoriatic arthritis.". Current Rheumatology Reports. vol. 14. 2012. pp. 349-57.(A detailed discussion of the mechanisms that underlie pathologic bone resorption and new bone formation in psoriatic arthritis.)
Coates, LC, Anderson, RR, Fitzgerald, O. "Clues to the pathogenesis of psoriasis and psoriatic arthritis from imaging: a literature review.". J Rheumatol.. vol. 35. 2008. pp. 1438-1442.(A comprehensive review of the merits and weaknesses of various imaging modalities in the diagnosis and management of psoriatic arthritis.)
Ritchlin, CT, Colbert, R, Gladman, DD. "Psoriatic Arthritis.". New Eng J Med.. vol. 376. 2017. pp. 957-970.(A timely review of the etiology, pathophysiology, clinical presentation and treatment of psoriatic arthritis.)
Gladman, DD, Antoni, C, Mease, P, Clegg, DO, Nash, P. "Psoriatic arthritis: epidemiology, clinical features, course, and outcome.". Ann Rheum Dis.. vol. 64. 2005. pp. ii14-17.(Concise and well-written review of psoriatic arthritis that references major works in the field.)
Ogdie, A, Haynes, K, Troxel, AB. "Risk of mortality in patients with psoriatic arthritis, rheumatoid arthritis and psoriasis: a longitudinal cohort study.". Ann Rheum Dis.. 2012.(A careful analysis of mortality in psoriatic arthritis derived from the THIN database in Great Britain.)
Coates, LC, Kavanaugh, A, Mease, PJ. "Group for research and assessment of psoriasis and psoriatic arthritis: treatment recommendations for psoriatic arthritis 2015.". Arthritis Rheumatol 2016;Jan 8..(The treatment recommendations from Group for the Assessment of Psoriasis and Psoriatic Arthritis [GRAPPA] that is centered on treatment that takes into consideration the various domains of the disease and comorbidities.)
Gossec, L, Smolen, JS, Ramiro, S. "European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update.". Ann Rheum Dis.. vol. 75. 2016. pp. 499-510.(Revised treatment recommendations for psoriatic arthritis from EULAR that are primarily focused on therapies for inflammatory arthritis.)
Eder, L, Jayakar, J, Shanmugarajah, S. "The burden of carotid artery plaques is higher in patients with psoriatic arthritis compared with those with psoriasis alone.". Annals of the rheumatic diseases. vol. 72. 2013. pp. 715-20.(A very important manuscript that shows that Framingham risk factor stratification in psoriatic arthritis may greatly underestimate the extent of cardiovascular disease revealed by carotid imaging.)
Coates, LC, Moverley, AR, McParland, L. "Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a UK multicentre, open-label, randomised controlled trial.". Lancet.. vol. 386. 2015. pp. 2489-98.(A trial comparing a tight control vs a usual care strategy with DMARDs and biologic agents in psoriatic arthritis.)
Wendling, D, Prati, C. "Paradoxical effects of anti-TNF agents in Inflammatory Diseases.". Expert Rev Clin Immun.. vol. 10. 2014. pp. 159-169.(A review of paradoxical adverse events associated with anti-TNF agents.)
Copyright © 2017, 2014 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.