Diagnosing and treating psoriatic arthritis: an update.

BJD

British Journal of Dermatology

R E V I E W A RT I C L E

Diagnosing and treating psoriatic arthritis: an update W.H. Boehncke,1 A. Qureshi,2 J.F. Merola,2,3 D. Thacßi,4 G.G. Krueger,5 J. Walsh,6 N. Kim7 and A.B. Gottlieb8 1

Geneva University Hospital, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 14, Switzerland Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115, U.S.A. 3 Department of Dermatology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, U.S.A. 4 Comprehensive Center for Inflammation Medicine, University of L€ubeck, Ratzeburger Allee 160, 23435 L€ubeck, Germany 5 Dermatology, University Hospital, University of Utah, Clinic 28, 50 North Medical Drive, Salt Lake City, UT 84132, U.S.A. 6 University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, U.S.A. 7 Tufts Medical Center, 800 Washington Street, #231, Boston, MA 02111, U.S.A. 8 Tufts Medical Center, 800 Washington Street, #114, Boston, MA 02111, U.S.A. 2

Summary Correspondence Alice B. Gottlieb. E-mail: [email protected]

Accepted for publication 18 November 2013

Funding sources AbbVie Inc. funded medical writing assistance but had no role in the content of the manuscript.

Conflicts of interest See the Appendix DOI 10.1111/bjd.12748

Psoriatic arthritis (PsA) is an inflammatory arthritis of uncertain pathogenesis, affecting approximately one in four patients with psoriasis. Onset of psoriasis typically precedes the development of PsA. Therefore, the dermatologist is ideally positioned to recognize the early signs and symptoms of PsA for diagnosis and subsequent treatment. The role of the dermatologist in early diagnosis and treatment is essential for preventing pain and functional disabilities, as well as the joint deterioration that accompanies progressive forms of PsA. Diagnosis of PsA is a key aspect of the clinical decision process for the dermatologist, as psoriasis plus PsA requires a different therapeutic approach from that required for psoriasis alone. Furthermore, PsA is associated with an increased risk of cardiovascular comorbidities that present significant health concerns. In this review, the pathogenesis and comorbidities of PsA are discussed. In addition, screening and imaging tools that aid in the diagnosis of PsA, as well as tools used for efficacy assessment, are reviewed. Available therapies are presented, with a focus on targeted biologics and emerging treatments.

What’s already known about this topic?

• • • •

Psoriatic arthritis (PsA) is a significant comorbidity of psoriasis. Physical disability, cardiovascular comorbidities, psychological issues, and a generally poor quality of life negatively impact many to most patients with PsA. Several tools have been developed to aid in PsA diagnosis and assessment. A large body of work has been devoted to researching factors contributing to PsA and developing targeted biologic therapies.

What does this study add?

• • •

772

Dermatologists are in a position to recognize the early signs of PsA and therefore can be instrumental in achieving the goal of early initiation of adequate therapy. Early intervention may also help slow disease progression and improve patient outcomes. This review may be used by dermatologists as an educational guide on the pathogenesis, screening, diagnosis, comorbidities, existing treatments and emerging therapies for PsA.

British Journal of Dermatology (2014) 170, pp772–786

© 2013 British Association of Dermatologists

Management of PsA, W.H. Boehncke et al. 773

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis that is uncommon in the general population (025% prevalence in the U.S.A.)1 but is quite common in patients with psoriasis (~25% prevalence worldwide).1–3 Psoriasis typically precedes the development of PsA by ~12 years;4,5 therefore, dermatologists are ideally situated to recognize and diagnose PsA in its early stages. Varied skin lesions accompany PsA, including localized, diffuse, guttate or pustular lesions. Among patients with psoriasis, nail dystrophy, scalp lesions, intergluteal/perianal lesions, and percentage of body surface area affected with psoriasis all appear to be associated with an increased risk for PsA.1,6 Erosive joint deformities have been reported in 40– 57% of patients with PsA;5,7 joint damage occurs in as many as 27% of patients within 10 months and in 47% of patients within 2 years of symptom onset.8 PsA has been placed in the family of spondyloarthropathies negative for rheumatoid factor, which includes ankylosing spondylitis, reactive arthritis and inflammatory bowel diseaseassociated arthropathy.9,10 PsA may afflict any synovial joint and the most common forms of PsA involve the joints of the hands and feet. PsA is characterized by swollen and tender joints, dactylitis [inflammation of an entire digit (‘sausage digit’)] and enthesitis (inflammation at sites of tendon insertion to bone), and axial involvement (inflammation in the sacroiliac joints or spine); inflammation may lead to progressive joint deterioration.5 PsA differs from other forms of inflammatory arthritis in that excessive bone is sometimes produced at joint margins; a diagnostic feature is the simultaneous presence of erosions and excessive bone within the same joint unit. In a combined effort, an international group of rheumatologists developed CASPAR (ClASsification criteria for Psoriatic ARthritis), a specific set of criteria for research (Table S1; see Supporting Information).11 Diagnosis of PsA using CASPAR requires peripheral or axial articular inflammatory disease or enthesitis and ≥ 3 points earned by assessing the following: evidence of skin lesions of psoriasis, past psoriasis, family history (the latter two weighted at half the points of a current psoriatic lesion), psoriatic nail dystrophy, rheumatoid factor negativity, dactylitis and specific juxta-articular radiological abnormalities.11 CASPAR was validated in patients with inflammatory arthritis and arthropathies.

Aetiology and pathogenesis The pathogenesis of PsA is complex, influenced by genetic, immunological and environmental factors. Familial aggregation of PsA was first noted in an English population.12 PsA certainly appears to be heritable – in Icelandic, Canadian and English populations, the risk in first-degree relatives of patients with PsA was 30–55-fold higher than for the general population.13– 15 Genetic and molecular techniques have established the association of PsA with the major histocompatibility complex, and several class I human leucocyte antigen (HLA) genes have been associated with specific PsA phenotypes. For example, HLAB27 has been associated with axial disease and HIV,16–19 while HLA-B38 and HLA-B39 have been associated with peripheral © 2013 British Association of Dermatologists

arthritis.20,21 Furthermore, PsA progression has been associated with HLA-B39 alone, HLA-B27 in the presence of HLA-DR7, and HLA-DQw3 in the absence of HLA-DR7.16–19 In contrast, patients with PsA with both HLA-Cw6 and HLA-DRB1*07 have been reported to have less severe PsA.22 The pathogenesis of psoriasis and PsA is mediated by inflammatory elements and the cytokine pathways they activate (Fig. 1).23,24 It has been proposed that the process leading to PsA starts at the enthesis (the point of insertion of tendons and ligaments in bone), where T cells, dendritic cells, mast cells, neutrophils and macrophages infiltrate the enthesium and synovium of joints in a manner similar to the processes that drive psoriatic skin lesions.25,26 Additionally, tumour necrosis factor (TNF)-a levels are elevated in the skin and synovium and are detectable in the plasma of patients with PsA and psoriasis.27,28 Recently, findings of increased Thelper (Th)17 cell counts in the circulation, synovial tissue and synovial fluid of patients with PsA have suggested that Th17 cells may be involved in the inflammatory response.24,29 Although the exact mechanisms of PsA are not yet elucidated, in models of autoimmune arthritis, overproduction of TNF-a, interleukin (IL)-17 and other inflammatory cytokines leads to osteoclastogenesis, bone resorption and cartilage destruction – changes that also occur in PsA.24,30,31 Additionally, studies conducted in a mouse model of spondyloarthropathy demonstrated that expression of IL-22 induces genes that upregulate entheseal and periosteal bone formation.32 Environmental factors also influence PsA development. Lifting heavy loads, bacterial infections, cigarette smoking and injuries may be associated with PsA;33,34 stressful life events have been identified as additional risk factors.35 Whether this mimics psoriasis onset following skin injury (Koebner response) remains to be elucidated.

Diagnostic and screening tools Psoriatic skin lesions usually precede the onset of joint symptoms; therefore, dermatologists are ideally situated to screen and diagnose PsA early in disease progression, thus mitigating many of its crippling elements. Dermatologists should ask their patients with psoriasis about signs and symptoms suggestive of an inflammatory arthritis like PsA, such as morning stiffness lasting > 30 min; typically, the arthritis symptoms of PsA improve with activity, but can present as hot, red, swollen joints.36 Dermatologists will want to query their patients about a family history of psoriasis or arthritis. During the physical exam, dermatologists should look for signs of PsA, such as joint swelling, dactylitis and enthesitis, as well as axial manifestations of PsA, such as pain, stiffness and range of motion limitations in the neck or back. Dermatologists may consider laboratory tests for some patients when screening for PsA. The acute-phase reactant C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated in approximately 50% of patients with PsA, and a lower level of ESR has been shown to reduce the risk of clinical damage progression.37,38 However, British Journal of Dermatology (2014) 170, pp772–786

774 Management of PsA, W.H. Boehncke et al.

Fig 1. Schematic presentation of immunological factors contributing to the pathogenesis of psoriatic arthritis. IL-12 induces differentiation of Th1 cells, while IL23 primarily stimulates proliferation and activation of Th17 cells, which are characterized by the expression of IL-17 A and F, IL-21 and IL-22.24 Cytokines produced by Th1 and Th17 cells induce the production of TNF-a in macrophages and other cell types, adding to inflammation. APC, antigenpresenting cell; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; TGF, transforming growth factor; Th, T helper; TNF, tumour necrosis factor. Adapted with permission from Raychaudhuri24

normal ESR and CRP findings do not preclude a diagnosis of PsA. In addition, dermatologists should ask their patients with psoriasis about enthesopathies (e.g. ‘tennis elbow’ and Achilles tendonitis). Enthesopathies are frequently observed in patients with PsA and sometimes are the only presenting rheumatic manifestation.39,40 Furthermore, questionnaires such as the Psoriatic Arthritis Screening and Evaluation (PASE; Fig. S1),41 the Toronto Psoriatic Arthritis Screening (ToPAS; Fig. S2)42 and the Psoriatic Epidemiology Screening Tool (PEST; Fig. S3; all provided as Supporting Information)43 were developed and validated by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) to facilitate diagnosis of PsA by dermatologists and rheumatologists (Table 1).41–49 Although these questionnaires allow early screening of PsA in

patients with psoriasis by dermatologists, recent validation studies demonstrated that these screening instruments have performed inconsistently with regard to specificity and sensitivity.47–49 Imaging is helpful for differential diagnosis, prognosis, monitoring disease progression and guiding therapy decisions. Imaging can be useful for diagnosis of axial disease (Fig. 2)50 and for establishing the severity of peripheral arthritis.51 Radiographs are useful for identifying typical proliferative and destructive bone lesions in PsA;52,53 baseline joint damage, if present, predicts further destruction.54 Ultrasonography and magnetic resonance imaging (MRI) are valuable for assessing synovial tissue, joint effusion, erosions, dactylitis, tenosynovitis and enthesitis.55–57 Imaging procedures are best

Table 1 Comparison of three screening tools for psoriatic arthritis

Based on Sensitivity Specificity Skin/nail assessment Axial disease ‘Active’ disease ‘Remission’ Marker of treatment Unique features

ToPAS42

PEST43

PASE41,45

Rheumatology, dermatology and methodology input 41–87%42,47–49 297–93%42,47–49 Yes Yes Yes Yes No Pictures of skin/nail involvement

Modification of PAQ by Alenius et al.46

De novo dermatology–rheumatology input and Delphi exercise 24–82%41,45,47–49 385–94%41,45,47–49 No Yes Yes No Yes Symptom and function subscales

275–92%43,47–49 372–98%43,47–49 Yes Yes Yes Yes No Figure of mannequin to indicate areas of soreness

PAQ, Psoriasis Assessment Questionnaire; PASE, Psoriatic Arthritis Screening and Evaluation; PEST, Psoriasis Epidemiology Screening Tool; ToPAS, Toronto Psoriatic Arthritis Screening. Adapted with permission from Qureshi et al.44




quately reflecting PsA disease activity in patients with oligoarticular and distal interphalangeal disease. Several questionnaires were developed to evaluate QoL in patients with PsA. The modified Health Assessment Questionnaire (HAQ)-Skin consists of questions from the original Stanford HAQ, used for QoL assessments in rheumatic diseases,66,67 as well as questions about psoriasis severity and functional impact.68 However, the HAQ-Skin does not adequately address the dermatological, social or psychological impact of PsA; the Psoriatic Arthritis Quality of Life (PsAQoL) is a reliable, easily administered tool developed to address this shortcoming.69 The negative psychosocial effects of psoriasis on mental health and QoL are well documented, especially regarding feelings of stigmatization, stress, anxiety and depression.70 Patients with PsA reported more bodily pain and role limitations due to emotional distress than patients with RA.71 Similarly, patients reported that PsA negatively affected mental health and social functioning.72

Comorbidities

Fig 2. A patient with psoriatic arthritis exhibiting asymmetric marginal and nonmarginal syndesmophytes (white circle) randomly distributed along the lumbar tract of the spine. Used with permission from Scarpa et al.50

performed in early disease stages, in consultation with a rheumatologist; physicians should appreciate that a negative finding for PsA does not preclude later onset.

Assessment tools The Outcome MEasures in Rheumatoid Arthritis Clinical Trials (OMERACT) and GRAPPA consortium achieved consensus on six core domains that should be assessed in clinical trials for PsA: peripheral joint activity, skin activity, pain, patient’s global assessment, physical function and health-related quality of life (QoL).58 Treatment efficacy tools for PsA include the American College of Rheumatology (ACR) score, the modified Disease Activity Score (DAS), PsA response criteria (PsARC), Disease Activity index for Psoriatic Arthritis (DAPSA), PsA Joint Activity Index (PsAJAI) and Composite Psoriatic Disease Activity Index (CPDAI); see Table 2.41,59–64 Additionally, GRAPPA recently developed two new composite measures that incorporate the assessment of joints, entheses, skin, dactylitis and axial disease. The Psoriatic ArthritiS Disease Activity Score (PASDAS) and Arithmetic Mean of Desirability Functions (AMDF) composite measures were better able to discriminate between high and low disease activity than the CPDAI, DAPSA and DAS28; further validation testing is underway.65 ACR and DAS are the most widely used assessment tools in clinical trials of PsA; both were originally developed for the evaluation of rheumatoid arthritis (RA). The DAS28 is limited by not ade© 2013 British Association of Dermatologists

PsA was initially considered benign, but is now known to increase the risk of cardiovascular disease, cerebrovascular disease, type II diabetes, hyperlipidaemia, hypertension and mortality.73–75 Although the risk of cardiovascular disease is increased with psoriasis alone, the risk is greater in association with PsA.76,77 Patients with PsA exhibit signs of subclinical atherosclerosis, demonstrated by increased carotid intima– media thickness.78–80 There may be a link between increased prevalence of cardiovascular disease in patients with PsA and metabolic syndrome, which encompasses overlapping symptoms, including obesity, impaired glucose tolerance and hypertension. Metabolic syndrome increases the risk of developing type II diabetes and atherosclerotic cardiovascular disease; in one study, metabolic syndrome was present in 58% of patients with PsA.81 Obesity has been associated with an increased risk of developing PsA82,83 and may be associated with an unfavourable response to therapy.84,85 Additionally, elevated levels of triglycerides, total cholesterol, high-density cholesterol and glucose have been reported in patients with PsA with subclinical atherosclerosis.80 Increased mortality of patients with PsA may be compounded by chronic obstructive pulmonary disease (COPD), which is more prevalent in patients with established PsA than in those with early-stage PsA.86 Although an aetiological relationship between PsA and COPD has not been fully identified, evidence shows an interplay between smoking status, genetic makeup and the prevalence of PsA in patients with psoriasis.87 Thus, interventions aimed at lifestyle modifications for preventing obesity or smoking are areas in which dermatologists can make an important impact early in the course of PsA. An important question, too early for an answer, is whether markers of and interventional treatment for these comorbid states will alter the natural history of psoriasis and PsA. It is interesting to note that treatment of RA with an anti-TNF agent has been associated with decreases in N-terminal probrain natriuretic British Journal of Dermatology (2014) 170, pp772–786

776 Management of PsA, W.H. Boehncke et al. Table 2 Comparison of psoriatic arthritis treatment efficacy assessment tools41,59–64 Tool

Disease domain

Instrument

Score range

ACR

Peripheral arthritis

66 SJC; 68 TJC PtPain PtGDA MDGDA Acute-phase reactants PtPain PtGDA MDGDA PtPain PtGDA MDGDA PtFunc (e.g. HAQ) Mathematical equation involving Ritchie Articular Index, total number of swollen joints, erythrocyte sedimentation rate and general health assessment General health assessment Total score Symptom score

66/68 VAS 10 cm VAS 10 cm VAS 10 cm

Function score 66 SJC; 68 TJC HAQ Acute-phase reactants Pt assessment Erythema Scaling MDGDA Enthesopathy index Tender/swollen digits Spondylitis Articular Index PtPain assessment 66 SJC; 68 TJC PtGA PtPain CRP Simplified instrument using weighted measures of a 30% improvement in each of: JNT, CRP, MDGDA, PtGDA, PtPain and HAQ MDGDA PtGDA PtPain MDGDA PtGDA PtPain HAQ 66 SJC; 68 TJC HAQ PASI DLQI Leeds enthesitis score HAQ Digit score HAQ BASDAI ASQoL

8–40 0–4 0–3

Dactylitis

Spinal disease

DAS

Physical function/disability Peripheral arthritis

Physical function/disability PASE

PsARC

Peripheral arthritis Enthesitis Dactylitis Spinal disease Physical function/disability Peripheral arthritis

Skin disease

Enthesitis Dactylitis Spinal disease DAPSAa


PsAJAI


Dactylitis

Spinal disease

CPDAI

Physical function/disability Peripheral arthritis Skin disease Enthesitis Dactylitis

Spinal disease

VAS VAS VAS VAS VAS VAS 0–3

10 10 10 10 10 10

cm cm cm cm cm cm

15–75 7–35

0–4 0–4 0–4 0–6 0–4 0–4 0–4 VAS 10 cm 66/68

0–9

VAS 10 VAS 10 VAS 10 VAS 10 VAS 10 VAS 10 0–3 66/68 0–3 0–72 0–30 0–6 0–3 0–20 0–3 0–10 0–18

cm cm cm cm cm cm

ACR, American College of Rheumatology; ASQoL, Ankylosing Spondylitis Quality of Life; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CPDAI, Composite Psoriatic Disease Activity Index; CRP, C-reactive protein; DAPSA, Disease Activity Index for Psoriatic Arthritis; DAS, Disease Activity Score; DLQI, Dermatology Life Quality Index; HAQ, Health Assessment Questionnaire; JNT, combined tender and swollen joint count scores; MDGDA, Physician Global Disease Activity Assessment; PASI, Psoriasis Area and Severity Index; PsAJAI, Psoriatic Arthritis Joint Activity Index; PsARC, psoriatic arthritis response criteria; Pt, Patient; PtFunc, Patient Function Assessment; PtGA, Patient Global Assessment; PtGDA, Patient Global Disease Activity Assessment; PtPain, Patient Pain Assessment; SJC, swollen joint count; TJC, tender joint count; VAS, visual analogue scale. aDomain

specifically indicated as peripheral arthritis only.




peptide, a biomarker for cardiovascular risk.88 A large retrospective study of patients from the Consortium of Rheumatology Researchers of North America (CORRONA) registry points to improvement with disease-modifying therapies, especially the anti-TNF agents, which were shown to modulate positively the risk and incidence of cardiovascular events.89

Treatment Disease severity influences the selection of an appropriate PsA treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy are commonly used to treat mild symptoms. The presence of PsA significantly impacts treatment decisions for patients with psoriasis, as several drugs indicated for RA may be ineffective for psoriatic skin lesions or even worsen symptoms. For example, systemic corticosteroids may be prescribed for short-term management of PsA, but are not recommended by dermatologists due to the risk of severe flares of psoriasis on treatment withdrawal. Likewise, some drugs, such as ciclosporin (see below), are very effective treatments for

psoriasis but are generally not effective in the treatment of most forms of PsA. Furthermore, the chronic nature of PsA and the increased risk of cardiovascular comorbidities necessitate comprehensive long-term management.90

Traditional nonbiologic disease-modifying antirheumatic drugs The American Academy of Dermatology, European League Against Rheumatism and GRAPPA have established treatment guidelines for PsA, including some therapies not currently approved for PsA (Table 3).51,91,92 Nonbiologic disease-modifying antirheumatic drugs (DMARDs) are recommended for patients with moderate-to-severe PsA. The synthetic DMARD methotrexate reduces inflammation by increasing the release of adenosine, a potent anti-inflammatory autocoid, at sites of inflammation.93 Methotrexate is commonly prescribed as an initial treatment for moderate-to-severe PsA; however, conflicting evidence exists regarding its efficacy in PsA disease modification. Methotrexate reduces joint tenderness and

Table 3 Available and emerging treatments for psoriatic arthritis

Drug

Class

Treatments approved for PsA Nonbiologic DMARD Methotrexate105,106 Leflunomide159 Nonbiologic DMARD Adalimumab101,106 TNF inhibitor Etanercept106,122 TNF inhibitor

Region(s) where approved for PsA

Golimumab106,123 Infliximab106,124

TNF inhibitor TNF inhibitor

Canada, Europe Europe U.S.A., Europe, Japan U.S.A., Canada Europe U.S.A., Europe, Canada U.S.A., Europe, Canada

Certolizumab pegol159,167

TNF inhibitor

U.S.A.

Ustekinumab155,159

IL-12/23 inhibitor

U.S.A., Europe

Treatments not approved for PsA Sulfasalazine116,159 Nonbiologic DMARD Ciclosporin A121,159 Nonbiologic DMARD Abatacept159,168 T-cell costimulatory inhibitor

Not applicable Not applicable Not applicable

Tocilizumab159,169 Secukinumab159–161 Brodalumab159 Apremilast164 Tofacitinib159,165,170

IL-6R inhibitor IL-17 inhibitor IL-17R inhibitor PDE-4 inhibitor Selective JAK inhibitor

Not Not Not Not Not

applicable applicable applicable applicable applicable

Dose Up to 25 mg per week (oral) 20 mg per day (oral) 40 mg SC every other week 50 mg SC every week 25 mg SC twice per week 50 mg SC every month 5 mg kg1 body weight IV at weeks 0, 2 and 6, and every 8 weeks thereafter 400 mg SC at weeks 0, 2 and 4, followed by 200 mg every other week; for maintenance dosing, can consider 400 mg every 4 weeks 45 mg SC initially and 4 weeks later, followed by 45 mg every 12 weeks. For patients > 100 kg with coexistent moderate-to-severe plaque psoriasis: 90 mg SC initially and 4 weeks later, followed by 90 mg every 12 weeks 2–3 g per day (oral) in two divided dosesa 25 mg kg1 per day in two divided dosesa,b 10 mg kg1 2 and 4 weeks after first infusion, then once per month IV or a single infusion loading dose (10 mg kg1), followed by 125 mg SC within 1 day, and 125 mg every week thereafterc 4–8 mg kg1 IV every 4 weeksc Up to 300 mg per month (SC)d 70–210 mg (SC) every 2 weeks or 280 mg (SC) monthlye 20 mg twice daily or 40 mg once daily (oral) 5 mg twice daily (oral)f

DMARD, disease-modifying antirheumatic drug; IL, interleukin; IV, intravenous; JAK, Janus kinase; PDE, phosphodiesterase; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SC, subcutaneous; TNF, tumour necrosis factor. aDose approved by the Food and Drug Administration (FDA) for RA; bdose approved by the FDA for psoriasis; cdose approved by the European Medicines Agency for RA; dinvestigational dose for RA; einvestigational dose for psoriasis; fdose approved by the FDA for RA.




swelling and suppresses skin manifestations, but the impact of methotrexate on radiographic progression remains unclear.94–96 More recently, the placebo-controlled Methotrexate in PsA (MIPA) study failed to demonstrate a significant advantage of methotrexate in modifying disease activity at 6 months, although global symptom measures improved.97 However, the MIPA study may have been underpowered, and the minimum entry criteria allowed for the inclusion of patients with active disease in fewer joints than in some other PsA trials. Another limitation of the MIPA study was the rate of patient withdrawal, which may help to explain the negative results. In contrast, methotrexate administered early in disease progression reduced joint inflammation compared with baseline in 68% of patients in a longitudinal cohort study.98 A recent meta-analysis reported that the addition of methotrexate to anti-TNF therapy in patients with immune-mediated inflammatory diseases reduced the development of antibodies against anti-TNF agents.99 Furthermore, methotrexate increases the serum concentration of infliximab and adalimumab.100,101 Methotrexate use has also been associated with a significantly decreased risk of cardiovascular disease in patients with psoriasis or RA.102,103 Therefore, adding methotrexate to TNF-inhibitor therapy may provide additional clinical benefit. Methotrexate is associated with the potential for a range of serious adverse effects.104–107 Methotrexate is a teratogen and abortifacient; it is contraindicated in women who are pregnant, attempting to conceive, or breastfeeding an infant. Methotrexate is also contraindicated in patients with alcoholism, alcoholic liver disease, other chronic liver disease, immunodeficiency or blood dyscrasias. Methotrexate should not be given to patients with renal impairment, hepatitis, cirrhosis, leuco-penia or thrombocytopenia. Acute toxicity due to drug– drug interactions may occur when methotrexate is administered to patients who are taking sulfamethoxazole plus trimethoprim, as well as some types of NSAIDs. A number of other substances may also interact with methotrexate; these include penicillins and many other antibiotics, hepatotoxic agents, theophylline and preparations of folate or its derivatives [e.g. folinic acid (leucovorin)]. Methotrexate-induced hepatotoxicity is a risk for patients with PsA, especially during long-term treatment.108 The consensus among dermatologists is to stratify patients on methotrexate as low risk or high risk. The latter category includes patients with pre-existing liver disease or other risk factors such as nonalcoholic steatohepatitis (NASH), excessive alcohol consumption, obesity and diabetes.91,104,109 NASH and nonalcoholic fatty liver disease associated with psoriasis (but not with RA) may confound identification of methotrexate hepatotoxicity.104,109 Liver function tests should be performed every 1–3 months in low-risk patients, and more often when starting therapy or changing the dose; monitoring procollagen peptide III is common outside the U.S.A.91,104 Opinions differ on whether the value of information from liver biopsy outweighs the risks of the procedure. Guidelines for PsA and psoriasis issued by the American Academy of Dermatology recommend considering liver biopsies for patients at risk for British Journal of Dermatology (2014) 170, pp772–786

methotrexate-induced hepatotoxicity.91 Biopsy may be warranted in high-risk patients after a cumulative oral methotrexate dose of 10–15 g and in low-risk patients after 35– 40 g.91,104 In contrast, the ACR guidelines for the use of methotrexate in RA do not recommend liver biopsy.110 Methotrexate may lead to myelosuppression and (more rarely) bone marrow failure and pancytopenia, although the chance of these complications is greater in patients with existing risk factors. The immunosuppressive nature of methotrexate therapy has been associated with developing malignancies. Lung disease such as pneumonitis may also occur during methotrexate therapy. Less serious but more common are gastrointestinal issues (ulcerative colitis, nausea, anorexia and stomatitis), leucopenia, fatigue, chills and fever, dizziness, susceptibility to infection, and malaise, which can sometimes be alleviated by folate supplementation or altering the route, number or timing of methotrexate doses. Although not approved for treating PsA, sulfasalazine has been examined in several clinical studies. Patients with PsA treated for 6 months with sulfasalazine showed improvement in clinical measures, including morning stiffness, number of painful joints, articular score and grip strength compared with placebo; however, skin manifestations did not improve.111–114 Most adverse events (AEs) associated with sulfasalazine were mild. In contrast, a subsequent small study suggested that sulfasalazine may not alter radiographic progression in PsA; additionally, due to gastrointestinal AEs, treatment was not well tolerated.115 Adverse gastrointestinal effects may make sulfasalazine treatment intolerable for some patients, although the incidence may be reduced at doses < 4 g per day. The use of sulfasalazine is contraindicated in patients with intestinal or urinary obstruction; porphyria (due to the risk of an acute attack); and hypersensitivity to sulfasalazine, its metabolites, other sulfonamide drugs, or salicylates.116 Caution must be used in treating patients who are breastfeeding and those with hepatic or renal damage, severe allergies or bronchial asthma, and blood dyscrasias. The anti-inflammatory drug leflunomide exhibited improvements in PsARC response and QoL compared with placebo in patients with PsA117 and resulted in modest but significant improvement in Psoriasis Area and Severity Index (PASI) scores and target lesion response.118 Due to the strong potential for fetal death and birth defects, leflunomide is contraindicated in pregnant women and women who could conceive, unless reliable contraception is used.119 Severe and occasionally fatal liver injury has occurred in some patients; therefore, leflunomide should not be given to patients who have existing liver disease or alanine aminotransferase > 2 9 the upper limit of normal. Caution is advised when leflunomide is coadministered with drugs, such as methotrexate, that also may be hepatotoxic, and in patients with chronic renal insufficiency. Leflunomide is a potential immunosuppressant and is not recommended in the settings of severe immunodeficiency, bone marrow dysplasia or severe, uncontrolled infections. Diarrhoea, nausea and hypertension were the most common AEs associated with leflunomide in clinical trials. © 2013 British Association of Dermatologists


Ciclosporin A (CsA) has demonstrated clinical benefit for psoriatic skin lesions, peripheral arthritis and axial symptoms in patients with PsA.120 However, direct evidence that CsA reduces radiographic damage is lacking. CsA is contraindicated in patients undergoing treatment with phototherapy, immunosuppressants (e.g. methotrexate), coal tar or radiation; it is also contraindicated in patients with abnormal renal function, uncontrolled hypertension and malignancies.121 CsA should not be given to women who are breastfeeding and should be used to treat a pregnant woman only if the benefits to her outweigh the risks to the fetus, which include premature birth and low weight. CsA has been placed in pregnancy category C. CsA can cause nephrotoxicity and renal dysfunction; thus, close monitoring of renal function is needed, particularly in elderly patients, in order to guide dose adjustments and avoid structural kidney damage. CsA can also cause hepatotoxicity. Blood pressure and laboratory parameters should be evaluated before starting treatment, monitored every other week during months 1–3, and checked every month thereafter. Similar to other immunosuppressive agents, there is an increased risk of lymphoproliferative malignancies and skin cancers (e.g. squamous and basal cell carcinomas) with CsA treatment. CsA is metabolized by cytochrome P450 3A enzymes and interacts with many substances, including calcium channel blockers, antibiotics, antifungals and grapefruit juice.121 The primary AEs associated with CsA therapy include hypertension, headaches, tremors, immunosuppression and nausea; other AEs include gum hyperplasia, hyperlipidaemia and hypertrichosis.

Biologic disease-modifying antirheumatic drugs Five TNF inhibitors-adalimumab, etanercept, golimumab, infliximab and certolizumab pegol-and one IL-12/IL-23 inhibitor, ustekinumab, are currently approved for the treatment of PsA (Table 3). TNF inhibitors improve cutaneous psoriasis, peripheral arthritis, QoL and function. Importantly, they slow or prevent structural damage in peripheral joints. In contrast to traditional DMARDs, TNF inhibitors exhibit efficacy for enthesitis, dactylitis and axial disease. Adalimumab, etanercept, golimumab, infliximab and certolizumab pegol share a number of safety considerations because of their common mechanism of action. Anti-TNF agents elevate the risk of opportunistic infections in general and have been associated with serious infections that can result in hospitalization or death.101,122–124 Treatment should not be started in a patient with an active infection; live vaccines should not be given concomitantly. The risk of infection may be greater in patients who are > 65 years of age or have weakened immunity due to comorbid disease or concomitant medications (e.g. methotrexate or corticosteroids). Besides new infections, reactivation of latent tuberculosis and hepatitis B virus infections may occur; all patients should be screened for tuberculosis and hepatitis B virus exposure. All five anti-TNF agents have been placed in Pregnancy Category B by the U.S. Food and Drug Administration and should be © 2013 British Association of Dermatologists

used in pregnant women only if clearly needed; it is unknown whether breastfeeding while on therapy is safe for the infant. Cautious consideration of risk and benefit is advised when considering adalimumab or other anti-TNF agents for patients with a history of malignancy due to associations with increased risk of developing malignancies, particularly lymphoma and skin cancer (mainly basal cell carcinoma and squamous cell carcinoma). In adolescents, cases of aggressive hepatosplenic T-cell lymphoma have been observed, although nearly all were in patients with Crohn disease or ulcerative colitis who were taking other immunosuppressants concurrently. Caution is advised in treating patients with demyelinating syndromes (e.g. multiple sclerosis) or congestive heart failure, due to the chance of new onset or exacerbation of symptoms. Psoriasis worsening or new onset may occur on beginning treatment with an anti-TNF agent. On rare occasions, a lupus-like disorder may result when autoantibodies form. Adalimumab is a fully human, anti-TNF monoclonal antibody. In the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), treatment with adalimumab resulted in significantly higher ACR20 response rates and significant inhibition of radiographic structural damage compared with placebo after 24 weeks.125 Radiographic damage was inhibited and clinical improvements were maintained in most patients at 48 and 144 weeks.126,127 Additionally, adalimumab significantly reduced the extent of psoriatic skin lesions and improved function and QoL.125,128 Adalimumab is generally well tolerated, with most AEs being mild to moderate in severity. Injection-site reactions were common in clinical trials, but most were mild, and they usually did not require the discontinuation of treatment.101 During 2 years of adalimumab exposure, the most common AEs were upper respiratory tract infection (URI), nasopharyngitis and sinusitis; serious infections and malignancies were observed at lower rates.127 Etanercept (fusion protein of soluble TNF receptor linked to human immunoglobulin Fc) is a receptor decoy and was the first TNF inhibitor reported to benefit patients with PsA. In a 12-week study, etanercept demonstrated efficacy for clinical measures of PsA and psoriasis, with significantly greater numbers of patients treated with etanercept achieving PsARC, ACR20 and PASI responses compared with placebo.129 In another study, etanercept significantly reduced disease activity, improved joint symptoms, reduced psoriatic lesions, and inhibited radiographic progression in patients with PsA.130 Two-year follow-up studies demonstrated sustained inhibition of radiographic progression and improved functional outcomes.131,132 Patients randomized to two different etanercept treatment regimens in the Psoriasis Randomized Etanercept Study in Subjects with Psoriatic Arthritis (PRESTA) trial exhibited significant improvements in skin, joints and QoL.133,134 A small observational study showed that etanercept improved axial manifestations of PsA.135 Etanercept was well tolerated in clinical studies; most AEs were mild to moderate. The most common AEs were injection-site reactions and URI.130,134 Golimumab is a fully human monoclonal anti-TNF antibody. In patients with active PsA (GO-REVEAL study), 48% of British Journal of Dermatology (2014) 170, pp772–786


patients receiving golimumab achieved an ACR20 response after 14 weeks, compared with a significantly smaller proportion (9%) receiving placebo.136 Golimumab improved skin and nail manifestations, physical function and QoL. Improvements in disease activity were maintained with longer treatment (52 weeks); additionally, golimumab inhibited radiological progression.137 AEs were similar to those associated with other TNF inhibitors and included nasopharyngitis and URI.136 The dosing and efficacy of golimumab for psoriasis have not yet been adequately studied. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) demonstrated the significant benefit of infliximab (chimeric anti-TNF monoclonal antibody) over placebo for improving measures of arthritis, dactylitis, enthesitis and psoriasis after 14–50 weeks.138–140 Longer treatment resulted in sustained improvement in joint and skin symptoms and inhibition of radiographic progression.141,142 Most AEs associated with infliximab were mild to moderate. After 2 years of treatment, the most common AE was URI.141 Infliximab is the only anti-TNF agent that is given via intravenous infusion and administered on a dose-per-weight basis. Infliximab doses of >5 mg kg1 are contraindicated in patients with moderate-tosevere heart failure.124 Infliximab is also contraindicated in patients with hypersensitivity to murine proteins. Infusion reactions occurred in 18% of patients treated with infliximab in phase III studies; however, < 1% of patients experienced a serious infusion reaction. Certolizumab pegol (pegylated Fab fragment of a humanized anti-TNF monoclonal antibody) demonstrated efficacy compared with placebo in patients with RA or psoriasis,143,144 and was recently approved for the treatment of PsA. In the RAPIDPsA study, ACR20 response rates were superior in patients treated with certolizumab pegol compared with placebo at weeks 12 and 24.145 Physical function was significantly improved after 24 weeks of treatment with certolizumab pegol, and improvements in psoriatic skin involvement, nail disease, enthesitis and dactylitis were also observed. Among patients treated with certolizumab pegol, the most common infectious AEs were nasopharyngitis and URI, while diarrhoea and headache were the most common noninfectious AEs. No head-to-head studies have compared anti-TNF agents for the treatment of PsA. Consequently, there have been attempts to determine the relative efficacy of these therapies via observational studies and analyses of separate well-controlled trials.120,146–151 Most research has suggested that improvements in joint manifestations of PsA were similar among the antiTNF agents. In several analyses, infliximab was more effective than etanercept in achieving PASI responses.120,147,149 Some analyses have shown that adalimumab may also be more effective than etanercept in achieving PASI responses.120,149,152 The certainty of these results is limited by the open-label nature of observational studies and by the heterogeneity of meta-analyses due to varying study end points, treatment duration and patient characteristics. Ustekinumab is a human monoclonal antibody that was recently approved for the treatment of PsA. It targets the p40 British Journal of Dermatology (2014) 170, pp772–786

subunit shared by IL-12 and IL-23, thus blocking its interaction with the receptor and inhibiting downstream signalling pathways, differentiation and cytokine production. Ustekinumab improved joint tenderness, enthesitis, HAQ and PASI measures compared with placebo in patients with PsA.153 Most recently, the 1-year PSUMMIT 1 study demonstrated significantly more ACR20 responses at week 24 in patients with PsA who received ustekinumab 45 or 90 mg compared with placebo.154 Ustekinumab was generally well tolerated, with the severity of the most common AEs reported as mild to moderate; the most frequent AEs were URI, nasopharyngitis and headache.153 Potentially serious reactivation of previous infections is possible with ustekinumab; it should not be given to patients with clinically important active infections, and caution is needed in patients with a history of recurrent infections.155 Patients should be checked for active tuberculosis infection before starting ustekinumab. They should not be given live vaccines and should avoid other people who have been immunized recently with live vaccines. Genetic deficiency in IL-12 and IL-23 is associated with disseminated infections caused by mycobacteria, salmonella and bacillus Calmette–Guerin, but it is unknown whether IL blockade with ustekinumab carries the same risks. As with the TNF inhibitors, ustekinumab is classified as a Pregnancy Category B agent and should be used in pregnant women only if the benefits outweigh risks to the fetus; caution is advised when nursing, due to a lack of data on the presence of ustekinumab in human breast milk and its effects on infants. Ustekinumab may also increase the risk of malignancies; rapidly developing squamous cell carcinomas were observed in patients with risk factors during postmarketing surveillance. A single case of reversible posterior leucoencephalopathy syndrome occurred during ustekinumab treatment; the patient recovered with appropriate treatment.

Emerging treatments Other biologics and small-molecule compounds are under development to treat PsA (Table 3). Some of these compounds have mechanisms of action that do not target TNF and several have shown promising results in phase II and III trials. Abatacept blocks interactions between antigen-producing cells and T cells, thus inhibiting T-cell activation. A placebocontrolled phase II trial of abatacept in patients with PsA demonstrated significant improvements in ACR20 response rate, MRI-monitored joint erosion and synovitis, PASI score and QoL.156 The IL-6 inhibitors tocilizumab and ALD518 have demonstrated efficacy and tolerability in the treatment of RA in clinical trials.157,158 The IL-17 inhibitors secukinumab and ixekizumab, as well as brodalumab (which, in general, blocks the IL-17 family of cytokines from binding to the IL-17 receptor) have shown efficacy in the treatment of psoriasis and RA.159–161 Unexpectedly, secukinumab had limited efficacy for PsA in a phase II study;162 a more definitive phase II or III trial will need to be completed to determine whether this is indeed the case. © 2013 British Association of Dermatologists


Apremilast (phosphodiesterase-4 inhibitor) and tofacitinib (selective Janus kinase inhibitor) function by inhibiting cytokine signalling pathways. Apremilast has demonstrated clinical benefit in the treatment of psoriasis;163 results of a phase II study in patients with PsA have been reported164 and larger trials are underway. Tofacitinib has recently been approved for the treatment of RA.165

Conclusions PsA is among the most significant comorbidities associated with psoriasis, resulting in pain and deformities that limit function and reduce QoL. Additionally, patients with PsA are at greater risk for developing metabolic syndrome and cardiovascular disease and should be routinely monitored for cardiovascular risk factors.90 PsA may lead to progressive joint deterioration, which treatment may slow or prevent. Because psoriasis often presents years before the onset of PsA, the dermatologist is uniquely positioned to recognize the early signs of PsA. In many cases, dermatologists may choose to work closely with rheumatologists to minimize symptoms, slow disease progression and maximize QoL. Many treatment options are currently approved for PsA, with biologic DMARDs producing significant improvements in disease activity and progression. Interestingly, antiTNF therapy was recently shown to improve cardiovascular comorbidities associated with PsA,166 suggesting clinical benefit beyond treating joint symptoms and supporting a comprehensive approach to long-term care.90 Several additional biologics targeting inflammatory pathways are currently under investigation for the treatment of PsA.

Acknowledgments AbbVie funded development of the publication by Complete Publication Solutions (CPS). Amanda L Sheldon PhD, of CPS, provided medical writing and editorial support to the authors in the development of this publication. AbbVie had no role in content development of the publication. All decisions regarding content were made by the authors.

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Appendix Conflicts of interest W.H.B. has current consulting/advisory board agreements with Biogen Idec, Janssen, Pfizer and MSD. A.Q. has current consulting agreements with AbbVie, Janssen, Novartis and the U.S. Centers for Disease Control; has licensed his questionnaire to Pfizer and Merck for clinical trials; and has received a research/educational grant from Amgen. J.F.M. is an investigator for Amgen and has a consulting agreement with Biogen Idec. D.T. has current consulting/advisory board agreements with Astellas, Biogen, Janssen, Celgene Corp., AbbVie, Pfizer, MSD and Lilly. D.T. receives research/educational grants (paid to the Department of Dermatology, Goethe University) from Pfizer. G.G.K., currently and in the past 2 years, has served on the steering committees for Centocor/Janssen for psoriasis and psoriatic arthritis and has given educational talks on these subjects. He also serves on the steering committees for PSOLAR/ Janssen and is compensated for these activities. G.G.K. chairs the data monitoring safety board for Pfizer for a new psoriasis indication and is compensated for these activities. He has given educational talks on psoriasis and psoriatic arthritis and has received fees and/or honoraria for these as well as for



services as a consultant or as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Lilly, L’Oreal, Medicis, Novo Nordisk and Vascular Biogenics Limited. J.W. has current consulting agreements with Celgene Corp. and AbbVie. N.K. has no relevant conflict of interests. A.B.G. has current consulting/advisory board agreements with Amgen Inc., Astellas, Janssen-Ortho Inc., Celgene Corp., Bristol-Myers Squibb Co., Beiersdorf Inc., Abbott Labs (AbbVie), TEVA, Actelion, UCB, Novo Nordisk, Novartis, DermiPsor Ltd, Incyte, Pfizer, Canfite, Lilly, Coronado, Vertex, Karyopharm, CSL Behring Biotherapies for Life, Merck & Co. Inc. and GlaxoSmithKline. She has received research/educational grants (paid to Tufts Medical Center) from Janssen-Ortho Inc., Amgen, Abbott Labs (AbbVie), Novartis, Celgene, Pfizer, Lilly, Coronado, Immune Control, Lerner Medical Devices Inc., Novo Nordisk and UCB.


Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s website: Table S1. CASPAR (ClASsification criteria for Psoriatic Arthritis) – specificity 987%, sensitivity 914%.11 Reproduced with permission from Cantini et al.171 Fig S1. The PASE (Psoriatic Arthritis Screening and Evaluation) questionnaire. Used with permission from Husni et al.41 Fig S2. The ToPAS (Toronto Psoriatic Arthritis Screening) questionnaire. Used with permission from Gladman et al.42 Fig S3. The PEST (Psoriatic Epidemiology Screening Tool) questionnaire. One point is scored for each question answered in the affirmative. A total score ≥ 3 is indicative of psoriatic arthritis. Used with permission from Ibrahim et al.43


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