An Integrated Approach For Psoriatic Arthritis.

Transcription

1 Review Article ISSN: Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), Available online through An Integrated Approach For Psoriatic Arthritis. Shaziya Tasneem*, K. V. Ratnamala R.B.V.R.R.women s College of Pharmacy, Barkatpura, Hyderabad,Andhra Pradesh,India. Received on: ; Revised on: ; Accepted on: ABSTRACT Psoriatic arthritis is a debilitating condition, which affects approximately the one-quarter of psoriasis patient. Psoriatic arthritis is a systemic, polymorphic joint disease with a variable presentation and clinical course. Psoriatic arthritis (PsA) is a systemic, polymorphic joint disease with the variable presentation and clinical course. The outcome depends upon the association with severe comorbidities such as diabetes, hypertension and dyslipidemia.this articles reviews about the recent advances done in psoriatic arthritis over a past several years with emphasis on early diagnosis for better understanding of pathogenesis and with new therapeutic approaches. There is lot of clinical laboratory and ultrasound features which help in identifying the patients destined to develop Psoriatic arthritis with the several screening tools which have been developed. It also recognized about the genetic and epigenetic factors, as well as T cells and cytokines, which plays a significant role in the pathogenesis of (PsA), and also several targets have been identified for therapeutic interventions. New therapies have been developed and also tested in Psoriatic arthritis and found to be highly effective for both skin and joint manifestations of the disease. The expectation is that, in future, Psoriatic arthritis patients can be treated early with more aggressively and that there will not be any significant progression of joint damage. KEY WORDS: Psoriatic arthritis, Screening tools, new concepts on genotype and phenotype relationships, Conventional treatments, new agents used for psoriatic arthritis. 1. INTRODUCTION Psoriatic arthritis is an inflammatory musculoskeletal disease which is psoriasis. Psoriasis is an inflammatory skin condition manifesting with scaly erythematous skin lesions which usually occurring on the extensor surfaces of the elbows, knees and which may also affect the scalp, inter-gluteal area, umbilical area, and other parts of the body [1]. It was first reported by Louis Aliberti in 1818, he had noticed an association between psoriasis and arthritis. Thus, it can be distinguished from other types of arthritis essentially because of the concomitant presence of skin involvement. 2-3% of the world population is considered to have isolated skin psoriasis, and arthritis might affect 5-42% of those patients, depends on the geographical region and severity of the skin findings [3]. The prevalence of Psoriatic arthritis is estimated to be around %.Approximately in 75% of the cases, the skin condition precedes arthritis and in 15% of cases, it appears after arthritis and in 10% cases, the skin and articular involvements are simultaneous. Usually, skin involvement appears around the age of years, while articular involvement appears two decades later [3]. In 1956, Wright defined psoriatic arthritis as a distinct entity based on the features due to lack of female predominance, the pattern of *Corresponding author Shaziya Tasneem R.B.V.R.R.women s College of Pharmacy, Barkatpura, Hyderabad, Andhra Pradesh,India. joint involvement, also due to absence of rheumatoid factors, and typical radiological features. Later he described about the clinical features of psoriatic arthritis. The American College of Rheumatology (ACR) accepted the entity psoriatic arthritis in The Moll and Wright were published classification criteria for Psoriatic arthritis in In 2008 CASPAR criteria (Classification Criteria for Psoriatic Arthritis), were developed to help early diagnosis of Psoriatic arthritis GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) is currently working on guidelines for research in psoriasis and Psoriatic Arthritis [7]. Until 2000, the treatment for Psoriatic arthritis was not very effective, despite the recognition of the prognostic factors; there was not much that could be done. However, with the advent of biologic therapy, potent treatments available for patients with Psoriatic arthritis. Moreover, recent studies have demonstrated that the early diagnosis is important. Additional therapeutic agents have become available such that the life of the patient with Psoriatic arthritis can now be modified 1. Although in past it was thought that the presence of nail psoriasis is correlated with the development of Psoriatic arthritis, but recent evidence does not support this [1].. 2. TYPES OF PSORIATIC ARTHRITIS: i. Symmetric Psoriatic arthritis: It affects several joints in pairs on both sides of body, like both elbows and both knees. It can be mild to severe. It can destroy joints over time,

2 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), and they may stop working, due to which the treatment is necessary. The symptoms of symmetric psoriatic arthritis looks like rheumatoid arthritis. ii. Asymmetric psoriatic arthritis:it typically affects only a few joints. They can be large or small and anywhere in body. Fingers and toes may swell like sausages. iii. Distal Interphalangeal Predominant (DIP): It mainly affects small joints at the ends of the fingers, toes and as well as the nails. Sometimes it s confused with osteoarthritis, what most of people think when they hear arthritis when the cartilage and bone in the joints wears away. iv. Spondylitis:It affects the backbone. It can cause inflammation and stiffness between vertebrae, the bones of neck, spine, and lower back and pelvis. It can also attack ligaments that connect muscles to bones and other connective tissue. accrued damage. If we treat patients aggressively with the appropriate medications to control inflammation and prevent damage in the first place, we can improve their quality of life function and allow a normal life span. A study performed at the University of Toronto Psoriatic arthritis clinic demonstrated that the patients who were reviewed in the clinic within 2 years of diagnosis fared better than those who were first evaluated in the clinic with longer disease duration. The longer the disease duration prior to the patient s first visit to the Psoriatic arthritis clinic, the higher the risk of developing joint damage. Haroon et al. demonstrated that even a 6 month delay in rheumatologic consultation resulted in worse outcome for patients of Psoriatic arthritis with higher health assessment questionnaire scores, more erosions, and sacroiliitis. Thus, it seems that the earlier Psoriatic arthritics patients are diagnosed, for the better outcome. v. Arthritis mutilans: It is the most severe and destructive form of psoriatic arthritis. Fortunately, it s rare. It badly damages the small joints of fingers and toes so that they become deformed. 3. CAUSES OF PSORIATIC ARTHRITIS: The people who have psoriasis will get psoriatic arthritis. Psoriasis is a skin disease that causes a red, scaly rash, often over the elbows, knees, ankles, feet, and hands. It can also affect your nails. It can happen because your immune system attacks the body instead of something from outside. Psoriatic arthritis usually shows up between ages 30-50, but it may start in childhood. Both men and women can be affected. 4. SYMPTOMS: In some people, symptoms may be subtle and show up gradually. For others, it can be sudden and dramatic. No matter which type of psoriatic arthritis you have, you may notice: Morning stiffness Painful, tender, stiff, or swollen joints Fatigue It can also cause inflammation in other areas, including your eyes. Mild arthritis may only have occasional flare-ups. But some people always have symptoms. This can cause permanent joint damage if it s not treated. People with psoriatic arthritis are more likely to be or become obese and have high blood pressure, high cholesterol, heart disease, and diabetes, too [9]. 5. IMPORTANCE OF EARLY DIAGNOSIS: We have also recognized recently that patients with this suffer from a number of comorbidities, many of which are precipitated by persistent inflammation. Patients with this have an increased frequency of cardiovascular disease, diabetes, the metabolic syndrome, and depression [1]. How do we diagnose psoriatic arthritis early? There are several clinical features which may identify the patients with psoriasis destined to develop arthritis. The extent of psoriasis is higher among those patients diagnosed with PsA compared to psoriasis patients without arthritis (psoriasis cutaneous [PsC]). However, most dermatologists believe that the scalp and inter-gluteal lesions are so common in psoriasis that they would not help to identify those patients who should be referred to a rheumatologist. On the other hand, nail lesions occur in over 80% of patients with Psoriatic arthritis compared to only about 40% of Psoriasis cutaneous patients [1,28]. CASPAR criteria: The CASPAR criteria help to identify PsA early However, these criteria is based on the stem of inflammatory musculoskeletal disease. Only rheumatologists can accurately make this type of diagnosis. To address this issue, the Group for Research and Assessment of Psoriasis and Psoriatic arthritics (GRAPPA) is developing criteria to identify the inflammatory arthritis which can be used by non-experts. Since it is not feasible for all patients with psoriasis to be reviewed by a rheumatologist, several groups have developed screening tools which can be administered to patients [18]. Need to diagnose Psoriatic arthritis early: As noted above, Psoriatic arthritis is associated with progressive joint damage which reduced quality of life and function and increased mortality. These are related to preceding joint inflammation and Screening tools for Psoriatic arthritis: A number of screening tools were developed specifically for patients with psoriasis to identify those who have Psoriatic arthritis. Two tools were developed for screening for PsA in the general population [22].

3 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), Biomarkers: Since psoriasis usually precedes the development of PsA, and dermatologists have difficulty in identifying inflammatory arthritis, it would be helpful if clinicians had a biomarker that would identify those individuals likely to develop the disease. In the past few years, we have seen several biomarkers for testing PsA. These include genetic, epigenetic, soluble, and cellular biomarkers [29,30]. Ultrasound: The use of ultrasound may be helpful in identifying the patients with PsA early, particularly among patients with psoriasis. Gisondi et al,

4 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), he performed an ultrasound study of entheses in 30 patients with psoriasis and 30 controls. They have be found that the entheses were thicker and the overall ultrasound score was higher in patients with psoriasis than in controls. They repeated the ultrasound assessment in the psoriasis patients for 2 years later, and three of the 30 patients had developed PsA. However, a study that compared ultrasound in patients with Psoriatic arthritis, patients with Psoriasis cutaneous and healthy controls found that obesity is a confounder in distinguishing between the groups [1]. Imaging: MRI is not only helping in assessing peripheral joints, but also axial (SI joints and spine) changes. For clinical trials Psoriatic arthritis MRI scoring (PsA MRIS) system has been validated by OMERACT (Outcome Measures in RA clinical trials). genetic association. There is familial clustering and higher concordance among monozygotic twins. The strongest association is with the MHC genes. It is possible that the MHC genes may be in linkage unequilibrium with disease susceptibility genes. The association of HLA B and HLA C is respectively stronger with Psoriatic arthritis and psoriasis. This unique inflammatory environment enables natural killer cell activation, suggesting a destructive role for natural killer cells which is activated by environmental stress signals during the initiation of Psoriatic arthritis. Furthermore, as IL-15 can reproduce the phenotype of joint natural killer cells from blood natural killer cells, this study demonstrated that the IL-15 is capable of priming resting natural killer cells in tissues to the effector phase [31]. Another important factor in managing Psoriatic arthritis, similarly to isolate skin psoriasis, is associated with a higher frequency of metabolic syndrome, increased cardiovascular morbidity and mortality, and a relative reduction in life expectancy when compared with that of the general population. Psoriatic individuals have increased prevalence in cardiovascular risk factors, such as diabetes mellitus, hypertension, dyslipidemia, smoking, obesity, and alcohol intake etc. And also in addition to reduced labor productivity, patients may also have higher levels of psychological stress and lack of satisfaction with their treatment. In a significant way, Psoriatic arthritis leads to physical and mental functional disability, in addition to decreased quality of life, comparable to that of Rheumatoid Arthritis patients. Thus, preventive measures and careful control of modifiable cardiovascular risk factors and of the systemic inflammatory process are mandatory in those patients [7]. 6. CONCEPT OF PATHOGENESIS: It is postulated in a genetically susceptible individual environmental factors (e.g. trauma, infection) triggers psoriasis and Psoriatic arthritis. PsA is characterized by synovitis, dactylitis, enthesitis, and ostetis. A common biomechanical factor is thought to be operative. Two diametrically opposite phenotypes; i.e destructive (erosions and osteolysis) and proliferative (periostitis and bonyankylosis) characterize the disease suggesting the involvement of both osteoclasts and osteoblasts in its pathogenesis with local factors (trauma infection) acting at the entheses and joints, determining the final outcome [7]. Genetics: GWAS6 (Genome Wide Association Studies) suggests psoriasis and Psoriatic arthritis to be heritable polygenic disorders with a stronger Psoriatic arthritis is an entheseal-based disease: Enthesitis may be a prominent clinical feature at presentation in up to 38% of PsA patients. Anatomical studies have shown that the enthesis is continuous with the joint structure and it also merges into the nail bed allowing for the development of concepts that link entheseal involvement with prominent features of PsA, both synovitis and nail dystrophic change. Furthermore, magnetic resonance imaging (MRI) studies have highlighted bone marrow oedema at sites of entheseal attachment in PsA, leading to the hypothesis that it may be micro trauma at entheseal sites that in genetically susceptible individuals leads to inflammation, as evidenced by bone marrow oedema, which then spreads to secondarily involve structures such as the synovium or the nail. Immunohistologic studies that have demonstrated both CD68 + macrophages and CD8 + T-cell infiltration at sites of entheseal inflammation add further weight to these concepts [4]. Environmental factors: The association between environmental factors and psoriatic disease has long been known. Streptococcus infection followed by pustular psoriasis has been described. More recently, two studies confirm the association between infection and the development of PsA. Pattisson et al. compared the prevalence of environmental exposures among 98 British PsA and 163 psoriasis patients over a window of exposure that ranged from 5 10 years prior to the onset of arthritis. They identified physical trauma, rubella vaccination, oral ulcers, and moving house were found to be associated with PsA. Subsequently, another case control study was performed by Eder et al. in which they administered structured questionnaires to 159 patients with recent-onset PsA and 159 patients with PsC and found that infections that required antibiotic treatment, injuries, and

5 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), occupations that involved lifting heavy weights were associated with PsA, while there was an inverse association with smoking. A population-based study identified obesity as a risk for developing PsA. Histopathology The synovium is infiltrated with T cells (CD 8, CD4), B cells, and monocytes. The expression of TNF-, IL1-, IL-6, and IL-18 is similar to that of RA. Presence of TH17 cells expressing IL-17 have been identified recently. There is increased vascularity, fewer T lymphocytes and greater in filtration of neutrophils than present in rheumatoid synovium.the histopathology resembles that of spondyloarthropathy than of rheumatoid arthritis [7]. Implications of newer findings on concepts of genotype phenotype relationships: There are several implications for the finding that certain HLA alleles and, most strikingly, particular haplotypes that are implicated in the susceptibility to develop PsA contribute differentially and often additively to the magnitude of different traits comprising the phenotype of PsA. Despite the relatively large size of this cohort, with 282 PsA cases clinically phenotype and sequence-based HLA typed to at least four digits, the study must be considered exploratory and requires validation in different ethnic groups, especially those with a greater admixture of populations having different principal ancestral haplotypes. In this way, the association of a particular allele within the context of a given haplotype can be better determined. It is interesting to note that the newer genetic findings are consistent with and appear to provide a molecular explanation for the long-held clinical observations of Moll and Wright, identifying entheseal predominant, synovial predominant and axial predominant as three of the major forms of PsA, with each now found to have differing HLA associations. The findings summarized in this review are also relevant to the discussion of pathogenic mechanisms in PsA. First, since different HLA molecules bind different peptides, they probably imply the presence of distinct autoimmune responses that are driving each of the phenotypes separately associated with different HLA alleles. As a corollary, the different peptides suggest that different proteins, perhaps with a different cellular distribution, are targets of these responses. Indeed, the finding that several different HLA alleles confer susceptibility to PsA is an argument in favour of an autoimmune hypothesis, since it directs attention to the different peptide binding properties of the molecules encoded by the susceptibility alleles. Secondly, one anticipates that these responses may be further distinguished by different predominant mechanisms that use one or another cytokine, and so forth, perhaps indicating that different drugs and biologics may be effective in different genetic subsets. These data also raise the possibility that there is a predominant type of target tissue involved in each separate process. Such an explanation of disease pathogens is goes some way to explain the consistent occurrence of dichotomous therapeutic responses whereby skin and articular structures, for example, respond with different magnitude or even direction to a given therapeutic agent (for example, cyclosporine, ustekinumab, IL-17 inhibition). Using the primary outcome measure of the American College of Rheumatology 20% (ACR20) improvement in clinical response, there is also a consistent degree of non responsive to any therapeutic agent (30 to 50%) suggesting that patients with certain clinical features will respond whereas other patients with other features will not. These observations are consistent with the hypothesis that discreet inflammatory pathways may operate across different tissue compartments [4]. Treatment Strategies: An adequate therapeutic approach of PsA depends on the type and severity of the skin and joint involvements. Based on comprehensive literature review and consensus opinion of 70 experts, including 54 rheumatologists and 16 dermatologists, Ritchlin et al., on behalf of GRAPPA, have established 19 recommendations regarding diagnosis, assessment and treatment of the five major clinical manifestations of PsA. Once established the diagnosis, the clinical form of arthritis and psoriasis should be characterized, aiming at providing the best treatment and final prognosis of the disease. Early specific therapy should be initiated to prevent functional disability and provide better quality of life. Thus, treatment should be individualized and provided by a multiprofessional team (rheumatologists, dermatologists, physiatrists, physical therapists, occupational therapists, ophthalmologists, and psychologists). Physical measures combined with rehabilitation, physical therapy and occupational therapy are essential adjuvant, and, when necessary, corrective surgeries should be recommended. Maintenance of a program of physical activity, postural orientation, stretching exercises and muscle strengthening with the practice of isometric exercises should be encouraged and gradually initiated, as inflammation is controlled with medication. Attention should also be paid to the intra-articular use of corticosteroids, because of the risk of joint contamination with bacteria present in skin psoriatic lesions, which require careful asepsis. The strategy of intra-articular infiltration can be useful to

6 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), control pauciarticular cases or when the patient had a good response to therapy, but maintained a few inflamed joints. Rarely, in refractory systemic cases, intravenous pulse therapy can be used [3]. For controlling moderate to severe peripheral arthritis, the use of leflunomide or sulfasalazine is recommended according to studies with level of evidence A. Methotrexate (MTX) at adequate weekly doses remains a good therapeutic option for controlling both skin and peripheral joint disease (level of evidence 2a and 2b: one or more controlled clinical, non-randomized trials). Cyclosporine, azathioprine, colchicines, and mycophenolate mofetil represent other alternative possibilities [32-34]. Anti-TNF agents such as etanercept, adalimumab, infliximab, golimumab, and certolizumab have been shown to safely reduce symptoms and inhibit the radiographic progression of joint space narrowing and bone erosion in PsA, and thus have become the gold standard for treatment. Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have led to improvements in PsA; however, clinical trials on brodalumab were discontinued due to a higher-than-expected incidence of suicide and suicidal ideation. It is unknown whether the risk of suicidal ideation applies to the entire drug class. Other drugs that interfere with the IL-17 pathway have not shown a similar association [2]. For skin manifestations, there is good level of evidence (recommendations 1a and 1b) for phototherapy, MTX, TNF-alpha inhibitors, efalizumab, cyclosporine, leflunomide, and sulfasalazine. For axial manifestations, the following are recommended (1a/b): NSAIDs, physical therapy, analgesia, sacroiliac infiltrations, and

7 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), TNF-alpha inhibitors. For enthesitis, TNF-alpha inhibitors are recommended as first line therapy (1a), and NSAIDs and other DMARDs can be used [32]. A recent systematic review summarizes therapies for PsA and provides the level of evidence for the efficacy of each of the drugs, together with their level of efficacy. Topical steroids for treating skin manifestations are subject to systemic absorption, producing desirable and undesirable effects. Disease-modifying anti-rheumatic drugs (DMARDs) are indicated in patients who have neither rapid nor satisfactory response to NSAIDs, or in the presence of radiological or functional progression [38]. Systemic corticotherapy hinders the control of skin manifestations, and, thus, should not be used only routinely, and only for a limited period of time. Systemic use of corticosteroids improves skin psoriasis, but their withdrawal triggers relapses in the form of rebound effect, producing recurrence of the skin manifestations or transformation into the generalized pustular form (von Zumbusch disease) [35]. For peripheral arthritis, GRAPPA recommends using DMARDs in monotherapy or in combination for at least three months, of which at least two months at standard target dose, although there is no evidence of efficacy of the combined therapy in PsA. In axial disease, a BASDAI decrease in six weeks suggests response to treatment. Biologics represent perspectives to the treatment of PsA [3]. The anti-tnf golimumab and the anti-il12/23 ustekinumab have shown improvement in dactylitis, enthesitis, and ACR 20. Physical therapy and motor rehabilitation are important and should be stimulated in each phase of the treatment [3]. A study is underway with abatacept; and alefacept, an inhibitor of the activation of pathogenic T cells, provided a reduction in the synovial cellular infiltrate. Surgical approach remains indicated for patients with sequelae and deformities due to the inadequate control of PsA. Thus, arthroplasties and other orthopedic interventions may be necessary [3]. In this study, patients with active PsA were randomized to ixekizumab 80 mg every 2 weeks, ixekizumab every 4 weeks, adalimumab 40 mg every 2 weeks, or placebo. The study demonstrated the efficacy of ixekizumab in controlling arthritis, skin and nail disease, dactylitis, and enthesitis as well as structural damage. This drug is now awaiting approval. More recently, the anti-il-12/-23 antibody ustekinumab was proven to be effective for PsA. While its efficacy for the arthritis is not quite as high as that of the anti-tnf agents, it works very well for the psoriasis. It does work for dactylitis and enthesitis as well. Next came the phosphodiesterase-4 (PDE4) inhibitor apremilast. Four phase III trials were carried out, demonstrating efficacy against placebo in patients with a history of conventional DMARD failure. Apremilast proved efficacious for peripheral arthritis, although not quite as effective as the anti-tnf agents. It was also effective for dactylitis and enthesitis. Based on the role of the Th17 axis in PsA, antibodies to the IL-17A cytokine were developed. Secukinumab was tested in two phase III placebo-controlled RCTs. The first, FUTURE-1, used 10 mg/kg secukinumab intravenously at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. FUTURE-2 included three doses: 75, 150, and 300 mg. While there were loading doses, in this study they were subcutaneous, not intravenous. The 75 mg dose did not work as well as the higher doses for the joints. The 300 mg dose was clearly better for the skin. Importantly, in both trials, secukinumab was effective for both Tumour necrosis factor inhibitor (TNFi-naïve and TNFi-experienced patients), although the 300 mg dose was more effective for the latter [1,39,40]. 7. ADVANCES IN THERAPIES FOR PSORIATIC ARTHRITIS: Conventional disease-modifying anti-rheumatic drugs (DMARDs) do not work well in PsA. A number of systematic reviews have been carried out and demonstrate that the effect size of methotrexate, sulfasalazine, and leflunomide are not very high and cyclosporine is toxic. Fortunately for PsA patients, TNF inhibitors (TNFi) became available at the beginning of the millennium and have demonstrated excellent efficacy in patients with PsA. Five TNFi agents are now available, including etanercept, adalimumab, infliximab, golimumab, and certolizumab [1]. Therapies under investigation: Several studies are currently ongoing in Psoriatic arthritis. Abatacept, or CTLA-Ig, a selective T-cell costimulation modulator that is approved for the treatment of rheumatoid arthritis, was initially tested in a phase II study which demonstrated efficacy as well as reduction in MRI inflammation. A phase III study has been completed and the results should be available soon. The Janus Kinase (JAK) inhibitor tofacitinib, also available for the management of rheumatoid arthritis, has also been tested in PsA.

8 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), The results of these studies will be available soon. An IL-23 antibody has also been tested in psoriasis and will be tested in PsA [1]. 8. THE LATEST ON TREATING PSORIATIC ARTHRITIS: Rheumatoid Arthritis (RA), novel antirheumatic agents were developed in large clinical trial programs at a breakneck pace. But only once their efficacy was formally established in RA, and usually after the drug had been brought to market, did clinical trial programs in PsA get under way seemingly as an afterthought. And indeed, many of the conventional and biologic disease-modifying antirheumatic drugs (DMARDs) that were approved for RA demonstrated efficacy in PsA as well and received formal approval. But again, this was usually after several years delay. All of a sudden, things have changed. A novel small-molecular agent with a unique mode of action, apremilast, has been approved for PsA and for psoriasis as well but with no prior experience in RA to speak of. Several biologics targeting the interleukin (IL)-17/23 pathway have been approved for psoriasis; one of these, ustekinumab, has been approved for PsA, and large clinical trial programs are under way with two other ones, secukinumab and ixekizumab. These developments have cast therapeutics for PsA into the rheumatologic spotlight, and we are likely to see very interesting developments over the next several years. 9. CONVENTIONAL TREATMENT FOR PSORIATIC ARTHRITIS: For patients with an RA-like form of PsA, the use of conventional DMARDs, although not supported by solid data from randomized trials, is nonetheless reasonable, and practical experience strongly suggests that such agents as methotrexate, sulfasalazine, and cyclosporine A can all be used with some efficacy in some patients. Some of these are also standard systemic therapies for psoriasis, and for patients with moderate or severe disease in both the skin and the joints, coordination with a dermatologist is often very helpful. First-line treatment for patients with milder forms of PsA can be nonsteroidal anti-inflammatory drugs, but as is the case in RA, these do not prevent damage and are therefore inappropriate as the sole therapy for patients with more severe forms of the disease. Corticosteroid injections and even short courses of oral steroids can be used as temporary measures, or for the management of simple flares in one or a few joints. 10. ANTI TUMOUR NECROSIS FACTOR FOR PSORIATIC ARTHRITIS: They are all effective for management of joint symptom and spinal symptoms, but their efficacy for the more PsA-specific manifestations, enthesitis and dactylitis, is not entirely clear. Dosing recommendations for peripheral and spinal PsA are the same as for RA and for ankylosing spondylitis, respectively. 11. NEW AGENTS FOR PSORIATIC ARTHRITIS: Recently, Apremilast (Otezla ) was approved for both psoriasis and for PsA. Apremilast is a small-molecular agent administered orally that inhibits phosphodiesterase 4 (PDE-4) and thereby inhibits inflammatory pathways. Apremilast is dosed at 30 mg twice daily, with an initial slow step-up. Its safety and tolerability appear to be good, with only limited need for laboratory monitoring. Nausea, diarrhea, and headache are common adverse events, especially during the first 2 weeks of treatment. Apremilast may increase the risk for depression and involuntary weight loss. Above Figure: Main efficacy outcomes of Apremilast at 16 weeks: American college of Rheumatology 20% improvement (ACR 20).

9 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), Ustekinumab (Stelara ) is a human monoclonal antibody that specifically binds a chain that is shared by both IL-12 and IL-23, thereby neutralizing the activity of both signaling molecules the latter being considered the more important one in PsA. Ustekinumab is administered subcutaneously at mg every 12 weeks (with starter doses at 0 and 4 weeks) and was approved in 2010 for the treatment of psoriasis. Above Figure: Main efficacy outcomes of ustekinumab at 24 weeks: American college of Rheumatology 20% improvement (ACR 20), B(ACR 50),C Psoriasis area severity index (PASI 75).

10 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6),

11 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), Above Figure: Main efficacy outcomes of secukinumab at 24 weeks: American college of Rheumatology 20% improvements (ACR 20), B (ACR 50), C Psoriasis area severity index (PASI 75). Ecukinumab (Cosentyx ) is a monoclonal antibody directed against IL-17A. It was recently approved for the treatment of psoriasis by authorities in both the United States and in Europe. In that disease, efficacy was demonstrated to be superior to placebo and also to etanercept. In PsA, a large phase 2 clinical trial did not achieve the trial primary endpoint, the ACR20 response after 6 weeks, but significant differences were noted for many secondary outcomes [5]. 12. ONGOING DEVELOPMENTS: Brodalumab targets the IL-17 receptor A and had shown very good efficacy both in psoriasis, where it was superior to ustekinumab, and in PsA However, one of the two companies sponsoring its development recently announced that it would pull out of the collaboration, citing a concern over suicidal ideation in patients in the trials. It is unclear whether the other company will continue developing it. Guselkumab, an IL-23-specific monoclonal antibody, is also currently being developed for PsA. Two additional monoclonal antibodies targeting the IL-17 pathway have been in phase 2/3 clinical trials for psoriasis or PsA. Ixekizumab is a humanized monoclonal antibody that binds and neutralizes both IL-17A and IL-17F. It has shown very good efficacy in psoriasis, and a recent press release stated that a large trial in PsA had achieved its primary endpoint [5]. 13. SUMMARY AND FUTURE DIRECTIONS: Recent advances in Psoriatic arthritis have emphasized that the disease is more common and more severe than previously thought. We know that even a 6-month delay in consultation with a rheumatologist results in untoward effects. A number of screening tools have been developed, which includes clinical features, screening questionnaires, and biomarkers, but an algorithm needs to be developed to accurately identify these patients early. New information on the pathogenesis of PsA has led to the development of new therapeutic interventions. Now we have several anti-tnf agents, anti-il-12/-23 agents, and anti-il-17 agents. Additional agents are currently under investigation and will hopefully be approved soon. Therefore, we can expect that patients with Psoriatic arthritics will be treated early and more aggressively that there will not be any significant progression of joint damage. Moreover, with effective treatment of the skin and joint disease and management of risk factors for the comorbidities, we can expect to reduce their occurrence and further reduce the excess mortality and reduced quality of life and function in these patients [1].

12 Shaziya Tasneem et al. / Journal of Pharmacy Research 2017,11(6), ABBREVATIONS: CASPAR: Classification of Psoriatic Arthritis; DMARD: Diseasemodifying anti-rheumatic drug; GRAPPA: Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; GWAS: genomewide association studies; HAQ: health assessment questionnaire; HLA: human leukocyte antigen; hs-crp: high-sensitivity C-reactive protein; IFN:interferon; IL-12B, interleukin 12 beta; IL-23R, interleukin 23 receptor; KIR: killer immunoglobulin receptor; MHC: major histocompatibility complex; MICA: major histocompatibility complex class I chain-related A; MMP-3: matrix metalloproteinase 3; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; NK: natural killer; OCP: osteoclast precursor; PsA: psoriatic arthritis; PsC: psoriasis cutaneous (cutaneous psoriasis without arthritis); RCT: randomized controlled trial; SF: synovial fluid; SNP:single-nucleotide polymorphism; TNF: tumor necrosis factor; TNFAIP3:tumor necrosis factor alpha-induced protein 3; TNFi: tumor necrosis factor inhibitor. REFERENCES: 1. Recent advances in understanding and managing psoriatic arthritis. Available at: NCBI Resources (file:///d:/new%20 folder/recent%20advances%20in%2 0understanding %20and%20managing%20psoriatic%20arthritis.html), pdf assessed 16 November, Immunologic Advances Reveal New Targets in Psoriasis and Psoriatic Arthritis. Available at: file:///d:/new%20folder/ Immunologic%20Advances%20Reveal%20New%20Targets%2 0in%20Psoriasis%20and%2 0Psoriatic%20Arthritis.html, 31 December, Current and relevant concepts in psoriatic arthritis. Available at: Jan or Feb, Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype Available at: Arthritis research and therapy.pdf assessed 7 May, The Latest on Treating Psoriatic Arthritis. Available at: Medscape Rheumatology, July 15, Psoriatic Arthritis: An Update Available at: Department of Internal Medicine, University of Chicago (NorthShore), 2650 Ridge Avenue, Evanston, IL 60201, USA Department of Dermatology, Baylor University Medical Center, Dallas, TX 75246, and USA.pdf assessed 13 October, Recent Advances in Psoriatic Arthritis from Obscurity to Prominence. Available at: Journal of association of physician of India volume 63, pdf assessed October Pharmacological treatment of psoriatic arthritis: a systematic literature review for the 2015 update of the EULAR recommendations for the management of psoriatic arthritis. Available at: ( pdf assessed 11 December, Psoriatic Arthritis: Overview, Available at:www. rheumatology. org, Gladman DD.: Clinical Features and Diagnostic Considerations in Psoriatic Arthritis. Available at: Rheum Dis Clin North Am. 2015; 41(4): Boehncke WH.: Etiology and Pathogenesis of Psoriasis. Available at: Rheum Dis Clin North Am. 2015;41(4): Treatment recommendations for psoriatic arthritis. Available at: Ann Rheum Dis. 2009; 68(9): Wilson FC, Icen M, and Crowson CS, et al.: Incidence and clinical predictors of psoriatic arthritis in patients with psoriasis: a population-based study. Available at: Arthritis Rheum. 2009; 61(12): Tinazzi I, Adami S, Zanolin EM, et al.: The early psoriatic arthritis screening questionnaire: a simple and fast method for the identification of arthritis in patients with psoriasis. Available at: Rheumatology (Oxford).2012; 51(11): Taylor W, Gladman D, and Helliwell P, et al.: Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006; 54(8): Chandran V, Schentag CT, Gladman DD: Sensitivity of the classification of psoriatic arthritis criteria in early psoriatic arthritis. Arthritis Rheum. 2007; 57(8): Mease PJ, Garg A, and Gladman DD, et al.: Development of simple clinical criteria for the definition of inflammatory arthritis, enthesitis, dactylitis, and spondylitis: a report from the GRAPPA 2012 annual meeting.j Rheumatol. 2013; 40(8): Chandran V, Schentag CT, Gladman DD. Sensitivity and specificity of the CASPAR criteria for psoriatic arthritis in a family medicine clinic setting. J Rheumatol 2008; 35: Chandran V, Cook RJ, Edwin J, et al. Soluble biomarkers differentiate patients with psoriatic arthritis from those with psoriasis without arthritis. Rheumatology (Oxford) 2010; 49: Gossec L, Smolen JS, Gaujoux-Viala C, et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis 2012; 71: A. Gottlieb, N. J. Korman, K. B. Gordon et al., Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics, Journal of the American Academy of Dermatology, vol. 58, no. 5, pp , 2008.

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