Steps in the management of psoriatic arthritis: a guide for clinicians

Abstract

Psoriatic arthritis is a common systemic inflammatory disorder, which in addition to skin and nail involvement may be associated with peripheral and axial joint involvement, enthesitis, dactylitis, and important comorbidities – especially cardiovascular morbidity. Better insights into the involved pathogenic mechanisms have resulted in an improved therapeutic armamentarium, which targets key pathways in its pathogenesis. This has resulted in significant clinical responses to newer therapeutic agents, especially those directed at inhibition of tumor necrosis factor α. Biological therapy leads to significant levels of remission, improved quality of life, and retards or improves structural radiological damage.

Introduction

This review primarily focuses on the pharmacological management of psoriatic arthritis (PsA). Table 1 outlines the steps to follow in the overall management of patients with PsA. In recent years, several reports have been published describing distinct therapeutic approaches for the management of PsA. In addition, several guidelines have been published by individual authors, research organizations, national and international societies. Most of these guidelines offer comprehensive approaches based on evidence obtained from a systematic review of the literature, consensus opinion, or personal experience [Ambarus et al. 2012; Saad et al. 2011; Gossec et al. 2012; Ravindran et al. 2008; Ritchlin et al. 2009; Salvarani et al. 2011]. A brief discussion of the pathogenesis of psoriasis and PsA follows.

Table 1.

Steps in the management of psoriatic arthritis: guide for clinicians.

Early and accurate diagnosis: CASPAR criteria

Define clinical domains involved:

Skin and nails

Peripheral joints

Axial joints

Enthesis

Dactylitis

Comorbidities

Define disease activity: ESR, CRP, imaging studies

Therapeutic considerations:

Nonpharmacological measures:

Patient education

Occupational therapy

Physical therapy

Pharmacological management:

Nonsteroidal anti-inflammatory drugs

Disease-modifying antirheumatic drugs

Biological therapy

TNFα inhibitors

T-cell costimulation modulation

Cytokine or receptor blockade

B-cell depletion therapy

CASPAR, Classification of Psoriatic Arthritis study group; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TNF, tumor necrosis factor.

Psoriasis and PsA are systemic disorders with a complex etiopathogenesis that involve the interplay of environmental, genetic, and innate and adaptive immune system factors. In addition, nonimmune mechanisms such as inflammasome activation, hypoxia and autophagy may also contribute to the associated comorbidities seen in these disorders. It has been clearly established that skin, nails, peripheral joints, spine, enthesis, and dactylitis are the main target organs of inflammation in these disorders.

Genetic factors

Evidence gathered from population-based family studies, candidate gene studies, as well as genome-wide linkage analysis and genome-wide association studies have shown greater heritability of PsA than psoriasis, at least three to five times higher than psoriasis. The strongest genetic association for psoriasis and PsA is with human leukocyte antigen (HLA)-C within the major histocompatibility complex (MHC) region. Other class I HLA antigens associated with PsA include HLA-B13, HLA-B27, HLA-B38, HLA-B39 and HLA-B57. Among subtypes of PsA, HLA-B38 and HLA-B39 are most strongly associated with peripheral arthritis, while HLA-B27 is associated with spondylitis. Regarding HLA class II molecules, HLA-DRB1*04 and HLA-DRB1*07 have been associated with PsA; however, these associations have not been consistently replicated [O’Rielly and Rahman, 2011; Winchester et al. 2012].

Immune mechanisms

Dendritic cells and macrophages

Immature and mature dendritic cells (DCs) and macrophages are present in inflammatory infiltrates of skin and synovium of patients with psoriasis and PsA, where they present antigens to T cells, remove necrotic/apoptotic cells, and most importantly, they can be a source of a multitude of cytokines and chemokines such as CCL19. Several regulatory molecules are involved in this process, such as intercellular adhesion molecule 1 (ICAM-1), lymphocyte function-associated antigen 3 (LFA-3) and cluster differentiation (CD)-80/86 in DCs and LFA-1, CD2 and CD28 in T cells. In addition, plasmacytoid DCs (pDCs), a main source of type I interferon (IFN), are also present in the skin. Myeloid dermal DCs are also increased in psoriatic lesions and induce autoproliferation of T cells as well as production of type 1 helper T cell (Th1) cytokines. Keratinocytes are responsive to DC-derived and T-cell-derived cytokines, including IFNs, tumor necrosis factor α (TNFα), interleukin (IL)-17, and IL-20 family of cytokines, and in turn they produce proinflammatory cytokines (IL-1, IL-6, and TNFα) and chemokines [IL-8 (CXCL8), CXCL10, and CCL20) and S100 proteins. Feedback loops involving keratinocytes, fibroblasts and endothelial cells contribute to tissue reorganization with endothelial cell activation and proliferation and deposition of extracellular matrix [Nestle et al. 2009; Raychaudhuri 2012; Schon and Boehncke, 2005]. Participation of cell-mediated immune responses in the pathogenesis of PsA is suggested by the demonstration in synovial fluid and peripheral blood lymphocytes of different natural killer surface markers and γ/δ T-cell receptor antigen [Spadaro et al. 2004]. Endothelium may also play a role in the pathogenesis of longstanding PsA as evidenced by the increased expression of certain adhesion molecules in PsA synovium related to the disease duration [Riccieri et al. 2002].

Abundant osteoclasts are present at the pannus-bone junction, with an increased expression of receptor activator of nuclear factor κB ligand, and decreased production of osteoprotegerin. Precursor osteoclastic cells have been reported to be increased in the peripheral blood of PsA, and characteristically decreased significantly following treatment with TNFα inhibitors [Viera Duarte et al. 2012].

T cells

In patients with PsA, most lymphocytes are CD4, and the CD4/CD8 ratio in the synovial compartment can be as high as 2:1. CD8 cells are more commonly found in enthesis. Psoriatic T cells predominantly secrete IFNγ and IL-17. Clinical trials with TNFα inhibitors have shown beneficial effects and have led to reduced inflammation and reduced numbers of Th17 cells. However, while blockade of inflammatory mediators has proved very effective, when treatment stops the remaining autoreactive memory-effector Th cells can be reactivated and perpetuate chronic inflammation.

B cells

B cells may be present in skin and joints, and occasionally forming primitive germinal centers; however, no convincing evidence for the presence of autoantigens exists. Clinically, there is a subset of patients with PsA with positive cyclic citrullinated protein (CCP) antibodies that seems to be associated with a more erosive disease [Raychaudhuri 2012; Viera Duarte et al. 2012; Chang and Radbruch, 2011]. Lower levels of immunoglobulin G anti-CCP antibodies have been found in the synovial fluid (p < 0.01) and serum (p < 0.005) in patients with PsA compared with patients with rheumatoid arthritis (RA), but these levels were no different to patients with osteoarthritis (OA). However, the presence or absence of anti-CCP antibodies did not discriminate a particular clinical subset [Spadaro et al. 2007].

Cytokines

IL-12/Th1/IFNγ/TNFα/IL-1 and IL-23/Th17/IL17 are the main immune pathways in the PsA disease process. High levels of p40 protein, which is a subunit of the IL-12 and IL-23 cytokines, are present compared with healthy controls. TNFα, IL-1, IL-6, IL-8 and IL-10 are also found in high levels in the synovial fluid of patients with early onset PsA. An Italian study also showed synovial fluid IL-12 and IL-13 levels significantly higher in patients with PsA than in patients with OA [Spadaro et al. 2002]. Another study showed that after therapy with methotrexate (MTX) and cyclosporine, the IL-6 serum levels were significantly reduced, while soluble IL-2 receptor were slightly reduced without reaching statistical significance, suggesting that disease-modifying antirheumatic drug (DMARD) treatment could affect some pathways of the cytokine network in PsA [Spadaro et al. 1998].

Phagocytes and DCs are the main producers of IL-12, which is crucial to Th1 differentiation. IL-12, via its receptor, activates STAT4 which upregulates IFNγ. Human studies with anti-IL12p40 have shown that this treatment downregulates type I cytokines and IL-12/IL-23 in lesional skin. IL-17 mainly induces cytokine and chemokine production of antimicrobial peptides by keratinocytes. IL-23 favors the proliferation of the Th17 pathway and consequent production of IL-22 and IL-6 that stimulates the proliferation of keratinocytes and neutrophil infiltration. Accumulated evidence also suggests a role for type I IFN as an inducer of pDCs, which are increased and activated in early psoriatic lesions and are major inducers of expression of MHC class I and II antigens [Mitra et al. 2012].

Treatment: pathogenesis oriented

The therapeutic targets in PsA are antigen- presenting cells (APCs), T cells, and cytokines, and treatment may involve (Table 2):

Table 2.

Disease-modifying antirheumatic drugs and biological drugs: where, why and how do they work in psoriasis/psoriatic arthritis?

	MTX	TNFα inhibitors	CTLA-4	Anti-IL23/17 axis	Anti-CD20
APCs	↓macrophages	↓ CD163		↓ DCs	↑ Apoptosis of PMNs
T/B cell	↓ T cells	↓ CD3	↓ T-cell and naïve T-cell activation	↓ Th1/Th17	↓ Subset of T cells/CD20 positive
		↓ CD4 (Th1)		↓ Memory T cells	↓ Circulating B cells; in secondary lymphoid organs?
		↓ CD8
		↓ Th17
Cytokines/adhesion molecules	↓ IL-8	↓ MMP-13		↓ IL-12/23 p40,but not IL-12 p35
	↓ E selectin	↓ MMP-3		↓ IL-1/8/10
	↓ ICAM-1	↓ ICAM-I		↓ TNFα
	↓ MMP-3	↓ IL-12/23		↓ MCP-1
		↓ IL-17		↓ IFN-ɣ
				↑ IL-5

anti-CD20, anti-cluster differentiation 20; anti-IL23/17 axis, anti-interleukin 23/17 axis; APC, antigen presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen 4; DC, dendritic cell; ICAM-1, intercellular adhesion molecule 1; IFN, interferon; IL, interleukin; MCP-1, monocyte chemotactic protein 1; MMP, matrix metalloproteinase; MTX, methotrexate; PMN, polymorphonuclear cell; TNF, tumor necrosis factor α.

1. downregulation of function and apoptosis of APCs;

2. inhibition of T-cell activation through inhibition of costimulatory molecules;

3. depletion or blockade of autoreactive memory T cells;

4. cytokine or receptor blockade.

The clinical spectrum and disease severity in PsA are wide, ranging from mild symptomatology that requires minimum treatment to a rapidly destructive and disabling course. However, despite the lack of a thorough understanding of the disease mechanisms in PsA, several approaches are available to control disease activity. Damage in PsA can be attributed to bone resorption/formation that can progress to ankylosis if left untreated. Response to treatment is also variable, and even anti-TNFα inhibition, the most effective class of therapeutic agents, is associated with a 30–40% primary failure in both randomized clinical trials and registry-based longitudinal studies [Galadari et al. 2003; Tobin and Kirby, 2005]. Treatment of PsA is mainly extrapolated from RA due to the lack of randomized controlled trials evaluating the impact of DMARD therapy in PsA. Observational studies of conventional DMARD therapy have shown no impact on structural damage.

First-line therapy in PsA includes the use of anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and at times low-dose prednisone given orally or by intra-articular glucocorticoid injections, always taking into account existing comorbidities, especially premature cardiovascular disease. NSAIDs have been shown to be effective for joint symptoms and bone turnover, but have no impact on skin lesions. NSAIDs should be given for the shortest period of time possible and the lowest dose due to their potential toxicity in this high-risk population. Data suggest that in PsA cyclooxygenase 2 inhibitors are as effective as nonselective NSAIDs. Local and systemic glucocorticoids (average dose <7.5 mg/day) may be a useful adjunctive therapy in localized disease, mono/oligoarticular, enthesitis, or dactylitis or single joint flares. Systemic steroid use may be associated with skin flares and should be used with caution, especially when treatment is being tapered for the potential worsening of skin [Gossec et al. 2012; Ritchlin et al. 2009].

Conventional or traditional disease-modifying antirheumatic drugs

DMARDs are indicated for the treatment of moderate to severe or refractory cases of PsA. Patients with active disease, defined globally as one or more tender and swollen joints and poor prognostic factors, particularly those with elevated acute phase reactants, radiographical damage or clinically relevant extra-articular manifestations, who have failed to respond to NSAIDs within 3 months, should be treated with DMARDs.

Delay in the start of DMARDs may lead to worse outcome. MTX, sulfasalazine and leflunomide can be effective for peripheral but not for axial disease, enthesitis or dactylitis. Observational controlled studies with sulfasalazine have shown no reduction in long-term joint damage. Similarly, the use of antimalarials and gold salts is not recommended, and there is little convincing evidence regarding the efficacy of cyclosporine in PsA. It has been shown that the probability of continuing to take cyclosporine is significantly lower and the rate of adverse events (AEs) is higher when compared with MTX or antimalarials [Spadaro et al. 1997].

Before starting DMARD therapy patients should be screened and have regular blood monitoring, usually every 3 months, including blood counts, liver function tests and serum creatinine (Table 3).

Table 3.

Disease-modifying antirheumatic drugs and biological drugs for the treatment of psoriatic arthritis: overview of side effects and monitoring: guideline for clinicians.

	Side effects	Screening/monitoring
MTX	Nausea, diarrhea, stomatitis, fatigue, alopecia, elevated liver enzymes, myelosuppression, pneumonitis, increased risk of infection	CBC, renal function, liver enzymes every 8–12 weeks
		Viral hepatitis B and C prior therapy
LFN	Nausea, diarrhea, rash, alopecia, pneumonitis, elevated liver enzymes	CBC, renal function, liver enzymes every 8–12 weeks
		Viral hepatitis B and C prior therapy
SSZ	Nausea, diarrhea, abdominal pain, rash, granulocytopenia	CBC, renal function, liver enzymes every 8–12 weeks
		Screen for G6PD deficiency
CyA	Nausea, abdominal pain, nephrotoxicity, hypertension, hypertrichosis	CBC, renal function every 8–12 weeks
TNFα inhibitors	Injection site reaction, infusion reaction, reactivation of latent TB, increased risk of serious bacterial and opportunistic infection	CBC, renal function, liver enzymes every 8–12 weeks
		Screening for prior TB exposure
		Viral hepatitis B and C
		Avoid in NYHA class III–IV heart failure
Abatacept	Infusion or injection site reaction, increased risk of serious bacterial infection	CBC, renal function, liver enzymes every 8–12 weeks
		Screening for prior TB exposure
		Caution in patients with COPD

CBC, complete blood count; COPD, chronic obstructive pulmonary disease; CyA, cyclosporine A; G6PD, glucose 6-phosphate dehydrogenase; LFN, leflunomide; MTX, methotrexate; NYHA, New York Heart Association; SSZ, sulfasalazine; TNFα, tumor necrosis factor α; TB, tuberculosis.

Methotrexate

MTX is a folate antagonist that has been used in PsA for over 50 years, can be highly effective for long-term, continuous therapy (15–25 mg/week) for clinical and laboratory control in moderate to severe PsA, and associated with some decrease in radiological progression. Based on a literature review MTX is the first choice DMARD recommended. Considerable interindividual variation in efficacy and toxicity occurs, it is relatively well tolerated with a discontinuation rate of about 30% at 4–5 years, primarily secondary to liver toxicity, and the dose required to achieve clinical efficacy varies. MTX toxicity and clinical response might be influenced by certain genetic polymorphisms, such as A allele of dyhidrofolate reductase (DHFR) and homozygosity for the minor allele of methylenetetrahydrofolate reductase (MTHFR) associated with increased liver toxicity. In addition, patients with psoriasis and PsA have an increased prevalence of obesity, metabolic syndrome (fatty liver), and excess alcohol intake, which favors liver toxicity. Liver function should be monitored but liver biopsy is not recommended. In the presence of significant liver function abnormalities or drop in blood counts, MTX should be temporarily tapered down or discontinued. A prospective, controlled study using MTX in PsA revealed lack of efficacy. Kingsley and colleagues performed a 6-month double-blind randomized placebo-controlled trial (RCT) comparing MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria. Other outcomes included American College of Rheumatology 20% improvement criteria (ACR20), 28-joint Disease Activity Score (DAS-28) and their individual components. A total of 462 patients were screened and 221 recruited. Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsA response criteria (PsARC), ACR20, or DAS-28. There were also no significant treatment effects on tender and swollen joint counts, erythrocyte sedimentation rate, C-reactive protein, Health Assessment Questionnaire (HAQ), and pain. The only benefits noted were reductions in patient and assessor global scores and skin scores at 6 months. The authors concluded that this trial of active PsA found no evidence for MTX improving synovitis. MTX doses used (15 mg/week) in the study are below the recommended for the therapy of this disorder [Kingsley et al. 2012]. Furthermore, there is still considerable debate regarding route of administration (subcutaneous versus oral dosing), initial dosing and escalation, and role of folic acid supplementation to improve tolerability.

Open-label treatment of 10 patients with PsA with MTX resulted in decrease in T cells and macrophages as well as reduced expression of IL-8, E-selectin, ICAM-1, and matrix metalloproteinase 3 (MMP3) after 6–12 months of treatment. The recommended starting dose of MTX is between 5 and 10 mg/week for the first week or two, followed by rapid escalation to obtain a therapeutic target dose of 15–25 mg/week. Folic acid supplementation is recommended, and initially oral administration is preferred. In the event of an inadequate response or poor gastrointestinal tolerance, subcutaneous dosing can be used. In general, there is no contraindication for the concomitant use of NSAIDs and MTX, but the use of anti-inflammatory doses of aspirin should be avoided [Colebatch et al. 2011].

Biological disease-modifying antirheumatic drugs

The introduction of TNFα inhibitors in the early 2000s has had a major impact on the therapeutic management of both psoriasis and PsA. These agents have been shown to have significant impact on most clinical manifestations, including skin and nails, peripheral and axial joints, enthesis, dactylitis and also on some of the associated comorbidities such as cardiovascular disease [Glintborg et al. 2011; Schett et al. 2011; Chen et al. 2012]. Biological agents are recommended for the management of severe, refractory or intolerant disease. Treatment failure should be considered when, in spite of therapy for a length of time appropriate to the drug profile, usually 3–6 months, the disease still remains active [Gossec et al. 2012]. Treatment response, however, is variable, as evidenced by the 20–50% of patients experiencing an inadequate response, or a relapse. It is highly likely that genetic factors and the complexity of the pathogenic mechanisms contribute to the clinical response observed. Genetic polymorphisms within the TNF promoter region are candidates for modification of the clinical efficacy and toxicity of anti-TNFα therapy; the 308G>A variant (rs 1800629) can alter the magnitude of the TNF secretory response, and affect circulating TNF levels [Ceponis and Kavanaugh, 2010]; Hebert et al. 2012; Ramirez et al. 2012].

The TNFα inhibitors most commonly used to treat PsA are adalimumab, etanercept, infliximab, and golimumab. All of these agents can induce remission, defined as minimal or no clinically detectable disease activity in the presence of continuing drug treatment.

Adalimumab

Adalimumab is a fully human anti-TNFα monoclonal antibody. Several RCTs have conclusively shown that adalimumab is effective and safe in the treatment of PsA. In the adalimumab effectiveness in psoriatic arthritis trial (ADEPT) study, which included 313 patients, adalimumab improved the Psoriasis Area and Severity Index (PASI) by 75% or more as well as ACR20 scores, promoted radiological inhibition and improved fatigue, function, and quality of life [Mease et al. 2009]. Van Kuijk and colleagues showed that adalimumab therapy in PsA is associated with a marked reduction in CD3 T-cell infiltration and MMP13 expression in synovial tissue that correlated with DAS-28 after 4 weeks of treatment [Van Kuijk et al. 2009]. The efficacy and safety of adalimumab or cyclosporine as monotherapy or combination therapy for patients with active PsA despite MTX therapy have been studied. The results from the study showed that a combination of adalimumab and cyclosporine is safe and seemed to produce major improvement in both clinical and serological variables in patients with severely active PsA and inadequate response to MTX. Doses of NSAIDs and corticosteroids were also reduced, and no new safety signals were observed [Karanikolas et al. 2011].

Etanercept

Etanercept therapy for PsA has also been shown to be highly effective and safe. Mease and colleagues performed the pivotal study that showed that etanercept is an appropriate therapeutic agent for psoriasis and PsA [Mease et al. 2000]. Etanercept can be used either as monotherapy or in combination with MTX treatment, but it has been shown that concomitant MTX treatment does not seem to be a positive predictor factor of anti-TNF drug survival in patients with PsA [Spadaro et al. 2008]. Subsequent RCTs also showed that etanercept treatment in PsA is able to induce significant improvement in joints, skin and nails, enthesis, dactylitis, quality of life and function, and inhibition of structural radiological damage [Prinz et al. 2011]. Etanercept has been shown to downregulate the Th17 pathway cytokines in the skin, most likely due to a decrease in expression of IL-23 by TNFα [Zaba et al. 2009].

Infliximab

Infliximab, a chimeric monoclonal antibody to TNFα has also been shown to be effective in PsA. In the induction and maintenance psoriatic arthritis controlled trial II (IMPACT II) study performed in 200 patients with PsA, infliximab improved the disease activity index, skin and function parameters (except fatigue, which was not assessed), and enthesitis and dactylitis [Kavanaugh et al. 2007]. The RESPOND study compared the efficacy and safety of treatment with infliximab plus MTX with MTX alone in MTX-naïve patients with active PsA. In this open-label study, patients 18 years and older with active PsA who were naïve to MTX and not receiving disease-modifying therapy (N = 115) were randomly assigned (1:1) to receive either infliximab (5 mg/kg) at weeks 0, 2, 6, and 14 plus MTX (15 mg/week), or MTX (15 mg/week) alone. The primary assessment was ACR20 response at week 16. Secondary outcome measures included PASI, DAS-28, and dactylitis and enthesitis. At week 16, 86.3% of patients receiving infliximab plus MTX and 66.7% of those receiving MTX alone achieved an ACR20 response (p < 0.02). Of patients whose baseline PASI was 2.5 or greater, 97.1% receiving infliximab plus MTX compared with 54.3% receiving MTX alone experienced a 75% or greater improvement in PASI (p < 0.0001). Improvements in C-reactive protein levels, DAS-28 response and remission rates, dactylitis, fatigue, and morning stiffness duration were also significantly greater in the group receiving infliximab. In the infliximab plus MTX group, 46% (26/57) had treatment-related AEs and two patients had serious AEs compared with 24% with AEs (13/54) and no serious AEs in the MTX-alone group. Treatment with infliximab plus MTX in MTX-naïve patients with active PsA demonstrated significantly greater ACR20 response rates and improvement in PASI of 75% or more compared with MTX alone and was generally well tolerated [Baranauskaite et al. 2012; Smolen and Emery, 2011].

It has been shown that in patients with PsA who respond to infliximab, etanercept, and adalimumab, clinical improvement and magnetic resonance imaging (MRI) changes correlate with a decrease in CD163 macrophages, polymorphonuclear cells, CD4 and CD8 T-cell numbers, MMP3, ICAM-1, and Von Willebrand factor expression in the synovium after 8 weeks of treatment.

Golimumab

Golimumab is another TNFα inhibitor approved in the USA in 2009 for use with or without MTX or other nonbiological DMARDs in adults with active PsA or active ankylosing spondylitis (AS). In the GO-REVEAL study, golimumab was administered subcutaneously every 4 weeks, showed that it was effective in reducing signs/symptoms of active PsA through week 24. At 1-year follow up of the GO-REVEAL study, patients with active PsA (at least three swollen and at least three tender joints) were randomly assigned to receive subcutaneous placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks through week 20. A total of 405 patients were randomized: 113 to placebo and 146 each to the golimumab 50 mg and 100 mg groups. Both golimumab groups were significantly different versus placebo. Radiographical benefit was maintained through week 52. Clinical efficacy, including improvement in joint and skin responses and physical function, was maintained through 1 year. The frequency/types of AEs were similar to those reported through week 24. In addition, treatment with golimumab inhibited structural damage progression and demonstrated continued clinical efficacy and safety through 1 year [Kavanaugh et al. 2012]. Boyce and colleagues reviewed the literature and concluded that golimumab is better than placebo in treating PsA, and it should be considered as the first or second TNFα inhibitor in combination with MTX for the treatment of PsA [Boyce et al. 2010].

Abatacept

Abatacept is a fully human costimulatory T-cell molecule (extracellular domain of CTLA-4 linked to a modified Fc portion of human IgG1 binds to the CD80/86 receptor on an antigen-presenting cell, thus blocking the second signal activation of the CD28 receptor on the T cell inhibiting T-cell activation). Mease and colleagues in a 6-month, double-blind, placebo-controlled phase II study analyzed the safety and efficacy of abatacept in 170 patients with PsA who had previously taken DMARDs, including TNF inhibitors. Patients were randomized to receive placebo or one of three doses of abatacept (from 3 mg/kg to 30 mg/kg) on days 1, 15, and 29 and then once every 28 days thereafter. The primary endpoint was ACR20 response on day 169, secondary endpoints were MRI scores for joint erosion, osteitis, and synovitis, scores on the disability index of the HAQ and the short-form 36 (SF-36) health survey, the investigator’s global assessment of psoriasis, the target lesion score, and the PASI score. Significant improvements in the ACR20 were found in patients treated with higher abatacept doses compared with placebo. Significant improvements were also found in the secondary endpoints of the MRI, HAQ, and SF-36 scores and in skin measures of both target lesion and PASI scores; no new safety issues were identified [Mease et al. 2011].

Miscellaneous biological agents

Several newer drugs are currently in the initial stages of development and testing in PsA, such as ustekinumab/briakinumab (anti-IL-12/23), ixekinumab/brodalumab (anti-IL-17), anti-IL-15, tofacitinib (anti-JAK3), and tocilizumab (anti-IL-6). Preliminary data for several of these compounds look promising, but further studies are needed to fully assess their efficacy and safety profile [Gottlieb et al. 2009; *Cuchacovich and Espinoza 2009; Papp et al. 2012; Leonardi et al. 2012]. Anakinra (IL-1R antagonist) studies in PsA have not shown consistent results, but this drug has been shown to be effective in some refractory cases of PsA [Jung et al. 2010]. Apremilast (phosphodiesterase-4 inhibitor) exhibited moderate efficacy (43% ACR20) in one study [Schafer 2012]. Rituximab (anti-CD20) also exhibited moderate efficacy against PsA, particularly in patients not previously treated with anti-TNF agents [Cohen, 2008]. However, there is at present insufficient evidence to support a recommendation of rituximab in patients with PsA.

Biphosphonates

Zoledronic acid (ZA) suppresses osteoclast recruitment, differentiation and function, and also promotes apoptosis. McQueen and colleagues studied the effect of ZA in patients with PsA using MRI to assess bone erosion, edema and proliferation. Patients with erosive PsA were randomized to receive 3-monthly infusions of ZA or placebo for 1 year. Clinical assessments and MRI scans were performed at baseline and 1 year. Pair MRI scans were available in 22 patients, including 6 who received ZA and 16 who did not. DAS-28 score and C-reactive protein fell over 12 months to a greater degree in patients on ZA than in non-ZA treated patients (p = 0.023). The MRI bone edema score decreased in the ZA group, but increased in the non-ZA group (p = 0.0056) with regression of bone edema at 13.5% of sites in patients with ZA versus 6.9% in non-ZA patients (p = 0.072). There was no difference between groups in change in MRI erosion score. ZA reduced the progression of MRI bone edema, indicating probable suppression of osteitis concordant with reduction in clinical measures of disease activity [McQueen et al. 2011].

Available evidence suggests an acceptable efficacy and safety profile of both NSAIDs and conventional DMARDs (especially MTX) in PsA [Soriano and Rosa, 2009]. More solid evidence, however, is available supporting the efficacy of anti-TNF agents in treating the signs and symptoms of PsA and reducing radiographical progression [Garcia-Valladares et al. 2012]. There are no appreciable differences in terms of efficacy in all available anti-TNF agents, and the safety profile also appears to be good and similar for all of them. However, caution should be exerted when using these drugs, and clinicians should be aware of the possibility that patients may develop infections, especially tuberculosis, and unusual granulomatous complications including sarcoidosis, Crohn’s disease, psoriasis, demyelinating disorders such as optic myelitis, and uveitis [Cuchacovich et al. 2008, 2011; Prinz, 2011; Girolomoni et al. 2012].

Pharmacoeconomic studies are needed to fully assess the cost effectiveness of anti-TNF therapy, but available studies suggest that these agents are cost effective [Woolacott et al. 2006].

Conclusion and future perspectives

The therapeutic management of patients with PsA should be tailored according to clinical manifestations of the disease, including comorbidities. Several important clinical and pathophysiological issues remain to be determined, such as better definition of disease activity indexes, concept of remission, participation of nonimmune mechanisms (inflammasome regulation, dysfunctional autophagy), management of comorbidities, role of combination biological therapy, and whether biological therapy should be initiated as early as possible [Ambarus et al. 2012; Saad et al. 2011; Cuchacovich et al. 2012; Harty and Veale 2010]. A better understanding of the molecular pathways operating in these disorders will undoubtedly result in the design of newer therapies. Current therapy is directed against immune-mediated mechanisms operating in these disorders, but newer therapeutic modalities will need to incorporate advances in the understanding of nonimmune mechanisms.