**Entrepreneurship and Intrapreneurship in Social, Sustainable, and Economic Development: Opportunities and Challenges for Future Research**

#### **Sebastian Aparicio 1,2,\* , Andreu Turro 3 and Maria Noguera 4**

Received: 7 October 2020; Accepted: 23 October 2020; Published: 28 October 2020

**Abstract:** Understanding entrepreneurship and intrapreneurship as engines of outcomes beyond economic terms, this paper introduces the Special Issue "Entrepreneurship and intrapreneurship in social, sustainable, and economic development". Institutions set the basis to analyze the role societies and organizations play in supporting entrepreneurial and intrapreneurial activity. Thus, we take a broad look at formal and informal institutions as those contextual components that are encompassed in a social progress orientation. Based on this, we discuss and provide examples about how entrepreneurship and intrapreneurship lead social, sustainable, and economic outcomes. Thus, in this paper and this Issue, we argue that it is necessary to consider those (institutional) antecedents and (developmental) consequences of entrepreneurship and its diversity as a simultaneous process. In addition to summarizing the main contributions of those articles contained in this Issue, we highlight some opportunities and challenges to further explore the role of entrepreneurship and intrapreneurship not only in economic development but also in social change and sustainability.

**Keywords:** institutions; entrepreneurship; intrapreneurship; national growth; firm growth; economic development; social change; gender equality; sustainability

#### **1. Introduction**

Today's crisis derived from COVID-19 has drawn the attention of many people from different areas. Scientists are looking for vaccines or medicine to diminish the negative effects of the virus; governments are reacting through different strategies (e.g., lockdown, more equipped hospitals, public aid for those unemployed, etc.) and new rules of the game (i.e., mandatory use of face masks, social distancing, etc.); banks are re-assessing loans system and interest rates; the educational sector is struggling to deliver education with quality despite the restrictions and constraints; and companies are doing their best to adapt strategies while preserving employment and surviving. One way or another, all these actors are showing an entrepreneurial capacity to creatively overcome the current situation. However, entrepreneurial activity is not only a reaction of this particular juncture. It has become a vehicle to solve problems beyond economic terms, reflecting the existence of institutions toward social progress [1,2].

As such, entrepreneurship is a research area that has been shaped thanks to insights from a variety of disciplines. Scholars have contributed to understanding the psychological, sociological, anthropological, managerial, and economic aspects of entrepreneurial activity [3]. Among these

contributions, academia has recognized the importance of institutions not only for entrepreneurship, but also for economic development [4]. Although most of the existing research focuses on traditional entrepreneurial activities [5], other types of new ventures have emerged to tackle different economic, humanitarian, and environmental problems [6]. Yet, there is still much room to keep exploring how other sorts of entrepreneurial activities can enhance economic, social, and sustainable development from an institutional perspective [7].

Although entrepreneurship is diverse in terms of its types and nature, particular gaps might exist, from sociodemographic characteristics, corporate dynamics, regional and national outputs, and environmental issues [8]. For example, finer connections between women's entrepreneurship [9], intrapreneurship [10], and sustainable entrepreneurship [11], among other (less explored) types of entrepreneurial activities and development might serve to improve our understanding of entrepreneurial behavior.

Considering that entrepreneurship does not emerge in isolation, there is also a lacuna regarding the role of the institutional context [12] in shaping individual decisions, not only for becoming entrepreneurs [13] but also for undertaking innovative projects within firms [10]. Hence, it is suggested that institutions may condition the identification of entrepreneurial opportunities that offer solutions for social and sustainable problems at the regional and country level [11].

Given these research opportunities, we openly invited scholars within all the main economics, management, and sustainability sub-disciplines, among other areas, to explore the influence of (formal and informal) institutions on gender issues, intrapreneurship (and corporate entrepreneurship), as well as on green entrepreneurial activity for social, sustainable, and economic development. Thankfully, this Special Issue collected literature reviews and empirical papers, characterized by cutting-edge discussions about entrepreneurship and intrapreneurship for a variety of outcomes related to development at the organizational, regional, and national levels.

This paper, apart from the introducing the Special Issue, revises in Section 2 the disparate literature on institutions and entrepreneurship (including intrapreneurship). Section 3 focuses on the role entrepreneurship and intrapreneurship play in social, economic, and sustainable development. Section 4 summarizes the main contributions of those papers in this Special Issue; and Section 5, in addition to concluding, discusses some future research avenues.

#### **2. Institutional Context for Entrepreneurship and Intrapreneurship**

North and Thomas [14] help us understand the development process through which institutions play a key role in influencing productive activities that are ultimately linked to economic outcomes. Despite this approach being mostly related to economic growth, the general concept of institutions as "rules of game" [12] opens the possibility to explore other social and environmental outcomes as a result of human interactions and decisions. For example, North [15] suggests that societies have different motivations toward progress. Accordingly, intentionality constitutes a key component that differentiates some countries and regions from others. According to North [15], open societies are those who create and align incentives for all members to be more productive, whereas limited societies create barriers for production, and hence, development. These incentives and barriers come mainly from what North [12] calls formal and informal institutions. The former refers to written laws and regulations, whereas the latter consists of culture and habits. Both formal and informal institutions act at different levels, implying that informal institutions are more general and less dynamic than formal ones, which are focused on particular aspects of the policy design, thus changing rapidly [16].

The complementary relationship between formal and informal institutions has called the attention of scholars in entrepreneurship research as it basically enables us comprehend that the context matters to influence decisions around entrepreneurial activity and new ventures' performance [17]. By considering entrepreneurship as a process [18,19], extant research has suggested that potential entrepreneurs may ultimately set up new ventures thanks to the social support [20]. Even in the event of an individual not being interested in creating a new business, this social support enables his or her to perform

any kind of activity in an entrepreneurial way (i.e., identifying a problem and offering a solution). In this case, societies as a whole are equipped with entrepreneurial potential [21], which is needed for potential entrepreneurship and entrepreneurial activity [22]. That is why institutions become relevant to understand the existing incentives that lead to the formation not only of traditional (or commercial) new ventures but also of other types of entrepreneurial activities with a social component [5]. In this regard, to a greater extent, institutions explain the main differences of entrepreneurship across regions and countries [23,24], as well as the emergence and need of gender [9,25], green or sustainable [11,26], immigrant [27], sport [28], and intrapreneurship [29], which are ultimately engines of development.

Particularly for intrapreneurship, there is a mixture of institutions in which the formal and informal context constitute the more external level [10]. It turns out that institutions at the organizational level [30] also condition the entrepreneurial employees' initiatives within existing companies. The societies' perception about the key role companies play in the economy as a whole, and especially in the formation of a corporate culture toward diversity, creativity, innovation, greenism, and social purposes, create an (organizational) environment that stimulates everybody within the company. Thanks to this, employees at different hierarchical levels may be motived to move forward entrepreneurial projects that not only help the company to grow but also the economy and society as a whole.

#### **3. Entrepreneurship and Intrapreneurship as Engines of Development**

#### *3.1. Social, Sustainable, and Economic Outcomes of Entrepreneurship*

Extant research has shown that if societies are oriented toward progress, then these societies provide a suitable environment for entrepreneurs, who in exchange, create social benefits [2,31]. Indeed, econometrically speaking, the existing loop (i.e., endogeneity) between entrepreneurship and development is overcome thanks to the presence of institutions that positively affect entrepreneurial activity in one way or another. Accordingly, plenty of evidence exists around institutions, entrepreneurship, and growth (Bjørnskov and Foss [4] and Urbano et al. [32] offer thorough literature reviews). However, there are still unanswered questions regarding the role of entrepreneurship in other aspects of the development process beyond income and productivity.

Important efforts have been made regarding analyses on social outcomes such as poverty reduction [33], inequality [34], inclusive growth [2], and gender equality [35]. Although it is not as abundant as compared to the analysis of traditional economic growth, this literature confirms that entrepreneurs have a social sense, implying that their decisions transcend materialism and the money-making mindset. Williams and Shepherd [6], for instance, show appealing cases about the existence of new ventures that are created to solve problems derived from natural disasters. Similar devastation is observed when civil wars and internal conflicts destroy world heritage and create social displacement. More than jobs or other assets, people simply lose everything. To survive, they migrate to other countries where cultural aspects are sometimes totally different. From this perspective, Honig [27] and Smallbone et al. [36] reflect on how immigrant entrepreneurship turns into a solution for immigrants and even for locals, who may know about different products, services, processes, etc. This social consciousness leads individuals to turn needs and problems into opportunities through entrepreneurship. Ruiz-Rosa et al. [37] provide a perfect example, in which it is demonstrated that social entrepreneurial orientation reacts when external shocks such as the COVID-19 pandemic take place. Similar behavior is observed when environmental problems are considered more than a simple externality. Scholars agree that environmental problems become social issues in both the short- (poor healthy, misuse and exploitation of natural resources, etc.) and long-term (next generations, extinction of species, etc.) [26].

Wigger and Shepherd [38] explain that collectivism is key to entrepreneurially using natural resources while keeping environmental and social consciousness. Although much remains to be done in terms of sustainable development, the idea that social support and consciousness can properly produce what we need, helps us to comprehend that what we do may affect others not just today but

also in the near future. Collective reflection entails the acceptance of everybody, regardless of religion, origin, gender, and race. In this regard, Holliday et al. [39] invite scholars to consider the importance of gender and immigration to achieve the social development goals. Accordingly, the role of women and immigrants in multilateral organizations, policymaking, private companies, entrepreneurship, and families (as the deepest root) constitute a key component of diversity, which leads to social and environmental outcomes. Hall et al. [40] recognize that entrepreneurial mindset may enhance the decision-making processes of all stakeholders in the society aiming at sustainability. This implies, however, that much more evidence on how entrepreneurship (and its diversity) at different levels leads to better humanitarian, economic, and environmental outcomes is needed.

#### *3.2. Instrapreneurship as a Source of Social, Sustainable, and Economic Change*

Particularly for the organizational level, DiMaggio and Powell [30] analyze how societies and, especially, organizations react when social norms and shared cultural habits exist. Depending on these institutions at the country and organizational levels, firms design strategies that are linked to the entrepreneurial mindset employees might have, hence, encouraging entrepreneurial action. Nevertheless, important uncertainty can cause imitation of harmful practices [41], which may destroy all intrapreneurial initiatives toward economic development. Wrongly oriented policies or ineffective institutions may encourage behavior that is not beneficial to the economy [42,43]. As a possible solution, DiMaggio and Powell [30] suggest that cognitive scripts and schemes serve to absorb information, which is needed to define productive projects within organizations. Thus, existing rules in a society and beyond condition the best entrepreneurial practices that organizations adopt.

There exist different examples showing how rules and norms define the way entrepreneurial actions take place within organizations. In this regard, intrapreneurship is helpful for entering internationalization processes, enhancing innovativeness, and increasing performance, among other outcomes (cf. De Falco and Renzi [44] and Klofsten et al. [45]). In this sense, this sort of entrepreneurial activity within organizations has emerged as a mechanism to generate not only profitable results for firms but also valuable solutions for the society [46]. Despite the discussion around intrapreneurship, there is also extant research suggesting that certain institutions at organizational and country level influence the quantity and quality of this type of entrepreneurial activity [45,47]. For instance, Audretsch et al. [42] and Turró et al. [10] show that intrapreneurial decisions and actions are negatively affected when over-regulations for labor mobility and business procedures exist. Usually, these sorts of institutions are imposed in developing countries, where entrepreneurial and intrapreneurial action may be associated with survival reasons rather than growth and wealth creation.

However, from a theoretical perspective, Patriotta and Siegel [48] raise a debate on the role of institutions in the way individuals judge the entrepreneurial process. Honig and Samuelsson [47] explain that the intrapreneurial planning process of identification and exploitation of opportunities depends on the institutional context that is created at the aggregated level, and most importantly at the intra-firm level. Taking into account the internal and external environment, intrapreneurs create patterns that better use their resources and capabilities as mechanisms to start an adaptation process for firm and social value creation [45,49]. In light of this discussion, a better understanding on how intrapreneurs should also think strategically to overcome institutional barriers is required. Even though the exploration of human resources such as scientists, managers, workers, and intrapreneurs in general, can be derived from internal approaches, the understanding of external factors such as cultural support, social learning and adaptation, etc., that influence firms' performance might be required to understand sustainability initiatives that intrapreneurs lead in order to create firm growth and social change [49].

Figure 1 conceptually depicts the role of institutions in creating entrepreneurship and intrapreneurship for social, sustainable, and economic development.

**Figure 1.** Integrating institutions, entrepreneurship, and intrapreneurship for development.

#### **4. Summary of the Papers in the Special Issue**

In this Special Issue about entrepreneurship and intrapreneurship in social, sustainable, and economic development, a variety of 14 articles cover all the elements raised in our main debate. For example, Martínez-González et al. [50] focus on institutions as antecedents of entrepreneurial intentions. In particular, this research shows that cultural aspects such as beliefs, social norms, and values influence motivation, self-efficacy, and intention among young students in Spain and Poland. As institutions are also observed at the university level, Jung and Lee [51] exploit a survey tool (i.e., CS-EMS) to explore differences in gender and programs (i.e., engineers vs. non-engineers). The main findings suggest that entrepreneurial mindset differs between the analyzed groups. A deeper level of institutions refers to the family support that shapes entrepreneurial intentions. In this regard, Georgescu and Herman [52] show that the entrepreneurial background of families constitutes a relevant institutional factor for students' perceiving entrepreneurship as a good career choice.

Moving from intentions to actions, in which social support is needed (particularly the family one), Escamilla-Fajardo et al. [28] reveal through an exhaustive literature review that extant research about sport entrepreneurship can be classified based on four clusters, namely (i) football, entrepreneurship, and social development; (ii) football, innovation, and management; (iii) football, efficiency, and new technology; and (iv) football, injuries, and innovation in rehabilitation. This research opens up questions on how entrepreneurial activity (and the formation of these clusters) takes place across time and space. In this regard, Litsardopoulos et al. [53] empirically demonstrate that individuals allocate time to self-employment based on gender characteristics and the place (i.e., urban and rural areas) they live. Certainly, time, dedication, and motivation matter to move forward projects regardless if these are new ventures or initiatives within existing companies.

Encouraging entrepreneurship within firms requires the understanding of the external and internal environment, which leads to the creation of different strategies to readapt the company itself when there is institutional change. In this sense, Butkouskaya et al. [54] explore the role of entrepreneurial orientation (EO) and integrated marketing communication (IMC) in SMEs' growth. Interestingly, this research finds important differences for these factors when comparing companies from Spain (as a developed country) and Belarus (as a developing one). The development stage of countries turns out to be an important characteristic of the environment. Hence, Seikkula-Leino and Salomaa [55] analyze the effect of entrepreneurial competences and organizational change in Finnish universities. Thanks to this research, intrapreneurial universities can be understood as those higher educational organizations where supervisors and employees are equipped with entrepreneurial thinking and action. Having these characteristics would lead to an increase in the efficiency of managerial as well as teaching activities. Similar results are found in Pei et al.'s [56] study, which demonstrates that learning absorption through entrepreneurial team cognition significantly influences firms' growth in China.

Learning and knowledge are, then, key aspects that entrepreneurship and intrapreneurship can use to deliver social, sustainable, and economic benefits for entrepreneurs and everybody else in the society. Being unaware of the institutional context, particularly regulations and processes, might bring negative effects to companies as well as the society. Jaramillo-Moreno et al. [57] bring this discussion to our attention by identifying that some community-based tourism enterprises in Ecuador have neither designed nor implemented managerial, financial, operational, strategic, and marketing plans. The fact that these elements of a business plan have not been considered might reduce the social goals of these enterprises, especially in areas that are highly dependent on the tourism sector. This is something Ertac and Tanova [58] confirm in their article. They shed some light on the importance of empowering women through entrepreneurship to increase their entrepreneurial mindset, which is useful for personal development and business growth. Accordingly, the aggregated results lead to social benefits in Cyprus, even under unfavorable contexts.

Ruiz-Rosa et al. [37] suggest that when context becomes unfavorable, social entrepreneurial intention might be negatively affected. However, Ruiz-Rosa et al.'s [37] research also shows that students are explicitly expressing a desire for becoming social entrepreneurs. This is similar to what Butkouskaya et al. [59] find when analyzing tourism students in Spain. Accordingly, institutional characteristics at the macro, but most importantly, at the university level, define the intention of students to becoming entrepreneurs oriented toward sustainability. Alwakid et al. [26] also bring to our attention the power of (informal) institutions to increase the level of green entrepreneurial activity. In particular, this research builds upon the importance of sustainable entrepreneurship for the achievement of the sustainable development goals in Saudi Arabia, where knowledge expansion and growth are taking place thanks to public investment in research and development (R&D). Dobrzanski and Bobowski [60] confirm that this does not happen only in Saudi Arabia but also in ASEAN countries. By using data envelopment analysis (DEA), these authors find that public expenditure in R&D has created different effects, highlighting, for example, the case of Hong Kong, Indonesia, Singapore, and the Philippines. Certainly, the way entrepreneurs and incumbent firms identify and manage knowledge defines the development path, in which social change and sustainability transcend the traditional economic growth perception. Table 1 summarizes all these contributions.

#### **Table 1.** Summary of the studies in this Special Issue.

#### **Table 1.** *Cont.*

#### **5. Conclusions and Ways Forward**

This paper has brought together entrepreneurship and intrapreneurship as mechanisms that translate the influence of institutions on outcomes beyond economic terms such as social change and sustainability. By using institutional economics [12], we have analyzed the roles formal (as regulations) and informal institutions (as social support) play in the formation and development of entrepreneurship and its diversity, which includes gender, immigrant, social, green entrepreneurship, and intrapreneurship. In particular, for the latter, institutions at the organizational level [30]

have served to complement the influence of contextual factors on (intra)entrepreneurial activity. This framework analysis has helped us explore the extant literature, examples, and gaps around the usefulness of entrepreneurship and intrapreneurship for social, sustainable, and economic development. These analyses have served to open up a debate in which different scholars have participated with outstanding evidence, discussions, and contributions, in which entrepreneurship and intrapreneurship have been explored through different types such as gender, green, community-based entrepreneurship, and intrapreneurship, among others.

Some challenges still exist when considering the causal chain running from institutions, entrepreneurship, and development. Although Wigger and Shepherd [38] have drawn our attention through the proper exploitation of natural resources as a source of opportunities for entrepreneurship, some other aspects that have been always there might also drive entrepreneurial projects that individuals and companies can lead. As academics, practitioners, and policymakers, we can learn from what the Dutch non-profit company called The Ocean Cleanup is doing to preserve the environment. This firm has identified not an opportunity but a problem that is getting worse year by year: the enormous amount of plastic in oceans and rivers.  The way we as a society support companies like this one may create higher motivation to come up with solutions for social, sustainable, and economic problems. In this regard, alliances between universities, companies, and governments may foster a solid environment and ecosystem for entrepreneurs in pursuit of outcomes beyond money-making goals.

This undoubtedly brings theoretical challenges as well. Therefore, one might think that the complementary relationship between institutions at the macro- [12] and meso-level [30] brings solid foundations not only for firm growth but also for social, sustainable, and economic development. This theoretical viewpoint may be helpful for those policymakers oriented toward entrepreneurship, firm growth, and development, as it motives a debate around the role of different types of institutions in entrepreneurial activity at different levels in the development process [4,7]. That is why we need a better understanding of how macro- and meso-institutions improve the decisions of policymakers, companies, and entrepreneurs before, during, and after entrepreneurial and strategic processes, which might take place in turbulent times (e.g., COVID-19, violence, natural disasters, etc.).

**Author Contributions:** All authors have contributed equally. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** The authors, as Guest Editors, acknowledge the constant support from Hulda Li, as well as all managing editors that handled submissions, review, and publishing processes. Also, special thanks go to the reviewers, who with their time and valuable suggestions contributed to the enhancement of those papers accepted in this special issue. The authors want to thank all those scholars who have participated with cutting-edge ideas in this special issue. Particularly, Sebastian Aparicio acknowledges Durham University Business School for constant support. Additionally, Sebastian acknowledges COLCIENCIAS Ph.D. programme (617/2013), as well as Sapiencia-Enlaza Mundos (Municipio de Medellín) for financial support during Ph.D. studies. Andreu Turro and Maria Noguera acknowledge the financial support from the project ECO 2017-87885-P (Spanish Ministry of Economy and Competitiveness).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

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**5.2 Anti-interleukin 22**

IL-22 is a pro-inflammatory cytokine produced by both Th17 and a new group of T cells known as Th22 cells; Th22 cells are known to induce epidermal hyperplasia and dermal

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 345

Antiga, E., Volpi, W., Chiarini, C., Cardilicchia, E., Filì, L., Manuelli, C., Parrochi, P., Fabbri,

Antoni, C., Kavanaugh, A., Kirkham, B., Tutuncu, Z., Burmester, G.R., Schneider, U., Furst,

Antoni, C., Krueger, G.G., de Vlam, K., Birbara, C., Beutler, A., Guzzo, C., Zhou, B., Dooley,

Antoni, C.E., Kavanaugh, A., van der Heijde, D., Beutler, A., Keenan, G., Zhou, B., Kirkham,

Bachmann, F., Nast, A., Sterry, W. & Philipp, S. (2010). Safety and efficacy of the tumor

Bagel, J. (2011). Adalimumab plus narrowband ultraviolet B light phototherapy for the

Bartelds, G.M., Wijbrandts, C.A., Nurmohamed, M.T., Stapel, S., Lems, W.F., Aarden, L.,

Biogen, Inc. (2003). Amevive package insert. In: *www.clinicaltrials.gov*, 28.05.2011, available

Boehncke, W.H. (2007). Efalizumab in the treatment of psoriasis. *Biologics*, Vol.1, No.3, pp.

Brennan, F.M., Chantry, D., Jackson, A., Maini, R. & Feldmann M. (1989). Inhibitory effect of

Bristol-Myers Squibb. (August, 2009). Orencia package insert. In: *www.orencia.com,*  28.05.2011*,* available from: *http://packageinserts.bms.com/pi/pi\_orencia.pdf*.

(IMPACT). *Arthritis and Rheumatism,* Vol.52, No.4, pp.1227-1236.

pp.767-774.

Vol.64, No.8, pp.1150-1157.

No.1, pp.35-47.

No.4, pp.366-371.

*9.pdf*.

301-309.

*Rheumatology,* Vol.35, No.5, pp.869-876.

*the Rheumatic Diseases,* Vol.69, No.5, pp.817-821.

arthritis. *The Lancet*, Vol.2, No.8657, pp.244-247.

P. & Caproni, M. (2010). The role of etanercept on the expression of markers of T helper 17 cells and their precursors in skin lesions of patients with psoriasis vulgaris. *International Journal of Immunopathology and Pharmacology,* Vol.23, No.3,

D.E., Molitor, J., Keystone, E., Gladman, D., Manger, B., Wassenberg, S., Weier, R., Wallace, D.J., Weisman, M.H., Kalden, J.R. & Smolen, J. (2005a). Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial

L.T. & Kavanaugh, A. (2005b). Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. *Annals of the Rheumatic Diseases,*

B., Tutuncu, Z., Burmester, G.R., Schneider, U., Furst, D., Molitor, J., Keystone, E., Gladman, D.D., Manger, B., Wassenberg, S., Weier, R., Wallace, D.J., Weisman, M.H., Kalden, J.R. & Smolen, J.S. (2008). Two-year efficacy and safety of infliximab treatment in patients with active psoriatic arthritis: findings of the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). *The Journal of*

necrosis factor antagonists. *Seminars in Cutaneous Medicine and Surgery*, Vol.29,

treatment of moderate to severe psoriasis. *Journal of Drugs Dermatology,* Vol.10,

Dijkmans, B.A., Tak, P.P. & Wolbink, G.J. (2010). Anti-infliximab and antiadalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study. *Annals of*

from: *http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsare DevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm08600*

TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid

inflammation via several transcription factors such as STAT3 (Nograles et al, 2009).  A phase I study to evaluate the efficacy and safety of ILV-094 in psoriasis has been recently completed, while it is currently ongoing a phase II trial for rheumatoid arthritis (Pfizer, 2010).

#### **5.3 Chaperonin 10**

Chaperonin 10 belongs to the heat shock proteins family and acts as a molecular chaperon, regulating protein folding. Several studies support its anti-inflammatory activity and its role in down-regulating the excessive immune response (van Eden, 2008). Recombinant Chaperonin 10 (Cpn10) mimics these activities and its efficacy in psoriasis has been evaluated by a single-center, double-blind exploratory study, showing a significant improvement in Cpn10-treated patients (Williams et al, 2008). Phase II trials have been completed for psoriasis, rheumatoid arthritis and multiple sclerosis (Golant & Gutman-Yassky, 2011).

#### **5.4 Small RNA drugs**

The use of RNA interference as a drug is one of the possible therapeutic strategies to target the pro-inflammatory cytokines involved in psoriasis, as shown by several phase I and II ongoing clinical trials (reviewed in Jackson et al, 2006). On the basis of their role in psoriasis, suitable mRNA targets are TNF, IL-20 and IL-23. A recent study showed that local small RNA therapy against TNF provided amelioration in psoriasis in a xenograft transplantation model (Jakobsen et al, 2009). These results indicate that RNA interference is a potential therapy in the treatment of inflammatory skin diseases. Nevertheless the main challenge for this kind of therapy remains the delivery of small RNA.

### **6. Conclusion**

The introduction of biological drugs in clinical practice has revolutionized the treatment of psoriasis and psoriatic arthritis in the last decade. Biologics have shown to be effective and to have an acceptable safety profile, but there is still a need to assess long-term toxicity through clinical experience and careful post-marketing surveillance.

### **7. References**

inflammation via several transcription factors such as STAT3 (Nograles et al, 2009).  A phase I study to evaluate the efficacy and safety of ILV-094 in psoriasis has been recently completed, while it is currently ongoing

Chaperonin 10 belongs to the heat shock proteins family and acts as a molecular chaperon, regulating protein folding. Several studies support its anti-inflammatory activity and its role in down-regulating the excessive immune response (van Eden, 2008). Recombinant Chaperonin 10 (Cpn10) mimics these activities and its efficacy in psoriasis has been evaluated by a single-center, double-blind exploratory study, showing a significant improvement in Cpn10-treated patients (Williams et al, 2008). Phase II trials have been completed for psoriasis, rheumatoid arthritis and multiple sclerosis (Golant & Gutman-

The use of RNA interference as a drug is one of the possible therapeutic strategies to target the pro-inflammatory cytokines involved in psoriasis, as shown by several phase I and II ongoing clinical trials (reviewed in Jackson et al, 2006). On the basis of their role in psoriasis, suitable mRNA targets are TNF, IL-20 and IL-23. A recent study showed that local small RNA therapy against TNF provided amelioration in psoriasis in a xenograft transplantation model (Jakobsen et al, 2009). These results indicate that RNA interference is a potential therapy in the treatment of inflammatory skin diseases. Nevertheless the main

The introduction of biological drugs in clinical practice has revolutionized the treatment of psoriasis and psoriatic arthritis in the last decade. Biologics have shown to be effective and to have an acceptable safety profile, but there is still a need to assess long-term toxicity

Abbott Laboratories. (March, 2011). HUMIRA package insert Abbott Laboratories. In:

Aggarwal, S., Ghilardi, N., Xie, M.H., de Sauvage, F.J. & Gurney, A.L. (2003).

Amgen, Inc. (February, 2011). Enbrel package Insert. In: *www.enbrel.com*, 28.05.2011, available from: *http://pi.amgen.com/united\_states/enbrel/derm/enbrel\_pi.pdf*.

*www.humira.com*, 28.05.2011, available from: *http://www.rxabbott.com/pdf/humira.pdf*.

Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. *The Journal of Biological Chemistry,* Vol.278,

challenge for this kind of therapy remains the delivery of small RNA.

through clinical experience and careful post-marketing surveillance.

Amgen , Inc. (2011). Pipeline. In: *www.amgen.com*, 28.05.2011, available from:

a phase II trial for rheumatoid arthritis (Pfizer, 2010).

**5.3 Chaperonin 10**

Yassky, 2011).

**6. Conclusion**

**7. References**

No.3, pp.1910-1914.

*http://www.amgen.com/science/pipe.html*

**5.4 Small RNA drugs**

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 347

De Pità, O., Nardis, C., Lupi, F., Luci, C.A., Frezzolini, A. & Pallotta, S. (2011). Modulation of

Ding, C., Xu, J. & Li, J. (2008).  Rates

Döffinger, R., Dupuis, S., Picard, C., Fieschi, C., Feinberg, J., Barcenas-Morales, G. &

Eli Lilly and Company. (April, 2011). A Study in Patients With Moderate to Severe Psoriasis.

Esposito, M., Giunta, A., Mazzotta, A., Babino, G., Talamonti, M., Chimenti, M.S. &

Feldman, S.R., Gordon, K.B., Bala, M., Evans, R., Li, S., Dooley, L.T., Guzzo, C., Patel, K.,

Foley, P.A., Quirk, C., Sullivan, J.R., Dolianitis, C., Hack, S.P., Thirunavukkarasu, K. &

Genentech USA, Inc. (April, 2011). Rituxan package insert. In:*www.rituxan.com,* 28.05.2011*,*

Genovese, M.C., Mease, P.J., Thomson, G.T., Kivitz, A.J., Perdok, R.J., Weinberg, M.A.,

drug therapy. *The Journal of Rheumatology,* Vol.34, No.5, pp.1040-1050.

*http://www.gene.com/gene/products/information/pdf/rituxan-prescribing.pdf.* Genentech, Inc. (2009). Voluntary U.S. market withdrawal of Raptiva® (efalizumab). In:

*http://clinicaltrials.gov/ct2/show/NCT01107457?term=LY2439821&rank=3*. Ellis, C.N. & Krueger, G.G. (2001). Treatment of chronic plaque psoriasis by selective

*Investigational Drugs,* Vol. 9, No.5, pp.515-522.

*Rheumatism,* Vol.54, No.8, pp.2368-2376.

*Pharmacology,* Vol.23, No.2, pp.503-509.

In:*www.clinicaltrials.gov,*28.05.2011*,* available from:

*Dermatology and Venereology,* Vol.24, pp.1135-1143.

*www.fda.gov*, 28.05.2011, available from:

*MedicalProducts/UCM149681.pdf*.

pp.903-909.

960.

available from:

Vol.345, No.4, pp.248-255.

Toll-like receptors in psoriatic patients during therapy with adalimumab. *International Journal of Immunopathology and Pharmacology,* Vol.24, No.1, pp.185-188.

for the potential treatment of autoimmune diseases. *Current Opinion in*

of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. *Arthritis and*

Casanova, J.L. (2002). Inherited disorders of IL-12- and IFNgamma-mediated immunity: a molecular genetics update. *Molecular Immunology,* Vol.38, No.12-13,

targeting of memory effector T lymphocytes. *New England Journal of Medicine,*

Chimenti, S. (2010). Continuous treatment of plaque-type psoriasis with etanercept: an observational long-term experience. *International Journal of Immunopathology and*

Menter, A. & Gottlieb, A.B. (2005). Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial. *The British Journal of Dermatology,* Vol.152, No.5, pp.954-

Cooper, J. (2010). Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence. *Journal of the European Academy of*

*http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHuman*

Medich, J. & Sasso, E.H. (2007). Safety and efficacy of adalimumab in treatment of patients with psoriatic arthritis who had failed disease modifying antirheumatic

*http://www.simponi.com/sites/default/files/pdf/prescribing-information.pdf*.

Cassano, N., Loconsole, F., Galluccio, A., Miracapillo, A., Pezza, M. & Vena, G.A. (2006).

Cassano, N., Loconsole, F., Miracapillo, A., Travaglini, M., Di Giuseppe, M.D., Congedo, M.,

Centocor Ortho Biotech, Inc. (2009). Stelara medication label. In: *www.fda.gov,* 28.05.2011*,*

Centocor Ortho Biotech, Inc. (December, 2010). Simponi package insert. In:

Chaudhari, U., Romano, P., Mulcahy, L.D., Dooley, L.T., Baker, D.G. & Gottlieb, A.B. (2001).

Chung, E.S., Packer, M., Lo, K.H., Fasanmade, A.A. & Willerson, J.T. (2009). Randomized,

Cooper, J.C., Morgan, G., Harding, S., Subramanyam, M., Majeau, G.R., Moulder, K. &

da Silva, A.J., Brickelmaier, M., Majeau, G.R., Li, Z., Su, L., Hsu, Y.M. & Hochman, P.S.

Dauden, E., Griffiths, C., Ortonne, J.P., Kragballe, K., Molta, C.T., Robertoson, D., Pedersen,

de Groot, M., Teunissen, M.B.M., Picavet, D.I., de Rie, M.A. & Bos, J.D. (2010). Reduction of

during etanercept treatment. *Experimental Dermatology,* Vol.19, pp.754-756.

Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a

double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure

Alexander, D.R. (2003). Alefacept selectively promotes NK cell-mediated deletion of CD45R0+ human T cells. *European Journal of Immunology,* Vol.33, No.3, pp.666-

(2002). Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells.

R., Estojak, J. & Boggs, R. (2009). Improvements in patient-reported outcomes in moderate-to-severe psoriasis patients receiving continuous or paused etanercept treatment over 54 weeks: the CRYSTEL study. *Journal of the European Academy of*

different inflammatory cell types of the innate immune system in psoriatic skin

*http://www.simponi.com/sites/default/files/pdf/prescribing-information.pdf*. Centocor Ortho Biotech, Inc. (February, 2011). Remicade package insert. In:

*Immunopathology and Pharmacology,* Vol.19, No.1, pp.225-229.

*Immunopathology and Pharmacology,* Vol.23, No.3, pp.797-802.

randomised trial. *The Lancet,* Vol.357, No.9271, pp.1842-1847.

(ATTACH) trial. *Circulation,* Vol.107, No.25, pp.3133-3140.

*Dermatology and Venereology,* Vol.23, No.12, pp.1374-82.

*www.simponi.com,* 28.05.2011*,* available from:

*www.remicade.com,* 28.05.2011*,* available from: *http://www.remicade.com/remicade/assets/hcp\_ppi.pdf.*

*Immunology,* Vol.168, No.9, pp.4462-4471.

675.

Once-weekly administration of high-dosage Etanercept in patients with plaque psoriasis: results of a pilot experience (power study). *International Journal of*

Galluccio, A., Buquicchio, R., Mastrandrea, V., Filieri, M., Raho, G., Pezza, M. & Vena, G.A. (2010). The role of etanercept on the expression of markers of T helper 17 cells and their precursors in skin lesions of patients with psoriasis vulgari Treatment of psoriasis with different dosage regimens of etanercept: preliminary results from the Tαranta Plastic Study Groups. *International Journal of*

available from: *http://www.accessdata.fda.gov/drugsatfda\_docs/label/2009/125261lbl.pdf.*

*http://www.gene.com/gene/products/information/pdf/rituxan-prescribing.pdf.*

Genentech, Inc. (2009). Voluntary U.S. market withdrawal of Raptiva® (efalizumab). In: *www.fda.gov*, 28.05.2011, available from: *http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHuman MedicalProducts/UCM149681.pdf*.

Genovese, M.C., Mease, P.J., Thomson, G.T., Kivitz, A.J., Perdok, R.J., Weinberg, M.A., Medich, J. & Sasso, E.H. (2007). Safety and efficacy of adalimumab in treatment of patients with psoriatic arthritis who had failed disease modifying antirheumatic drug therapy. *The Journal of Rheumatology,* Vol.34, No.5, pp.1040-1050.

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 349

Jackson, A.L., Burchard, J., Schelter, J., Chau, B.N., Cleary, M., Lim, L. & Linsley, P.S. (2006).

Jakobsen, M., Stenderup, K., Rosada, C., Moldt, B., Kamp, S., Dam, T.N., Jensen, T.G. &

Kavanaugh, A., Krueger, G.G., Beutler, A., Guzzo, C., Zhou, B., Dooley, L.T., Mease, P.J.,

Kavanaugh, A., McInnes, I., Mease, P., Krueger, G.G., Gladman, D., Gomez-Reino, J., Papp,

Kavanaugh, A., Mease, P., Krueger, G.G. et al. (2009b). Golimumab, a new human TNF

Against Rheumatism (EULAR) Annual Congress. June 10-13, Copenhagen. Kerbleski, J.F. & Gottlieb, A.B. (2011). Dermatological complications and safety of anti-TNF

Kimball, A.B., Gordon, K.B., Langley, R.G., Menter, A., Chartash, E.K. & Valdes, J. (2008).

Kimball, A.B., J. Zhong, J., Valdes, J.M. & Gordon, K. (2009). Retreatment efficacy and long-

Klotz, U., Teml, A. & Schwab, M. (2007). Clinical pharmacokinetics and use of infliximab.

Ko, J.M., Gottlieb, A.B. & Kerbleski, J.F. (2009). Induction and exacerbation of psoriasis with

American Academy of Dermatology (AAD), March 6-10.

*Clinical Pharmacokinetics,* Vol.46, No.8, pp.645-660.

*Treatement,* Vol.20, No.2, pp.100-108.

study. *Arthritis and Rheumatism,* Vol.59, No.2, pp.234-240.

Vol.40, No.11, pp.5.

No.2, pp.200-207.

sequence complementarity. *RNA,* Vol. 12, No.7, pp.1179-1187.

trial. *Annals of the Rheumatic Diseases,* Vol.66, No.4, pp.498-505.

*Arthritis and Rheumatism,* Vol.60, No.4, pp.976-986.

treatments. *Gut,* Vol.58, No.8, pp.1033-1039.

factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter

Widespread siRNA "off-target" transcript silencing mediated by seed region

Mikkelsen, J.G. (2009). Amelioration of psoriasis by anti-TNF-alpha RNAi in the xenograft transplantation model. *Molecular Therapy,* Vol. 17, No.10, pp.1743-1753. Jancin, B. (2009). IL-17A Blocker Shows Early Promise for Psoriasis. *Skin and Allergy News,*

Gladman, D.D., de Vlam, K., Geusens, P.P., Birbara, C., Halter, D.G. & Antoni, C. (2007). Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2

K., Zrubek, J., Mudivarthy, S., Mack, M., Visvanathan, S. & Beutler, A. (2009a). Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: Twenty-fourweek efficacy and safety results of a randomized, placebo-controlled study.

alpha antibody, administered subcutaneously every 4 week in psoriatic arthritis patients: 104-week efficacy and safety results of the randomized, placebocontrolled GO-REVEAL study. Abstract presented at the 2009 European League

Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial. *Archives of Dermatology,* Vol. 144,

term safety of the fully human, interleukin-12/23 monoclonal antibody ABT-874 in the treatment of moderate to severe psoriasis: 48 week results from a phase II trial to severe psoriasis: 48 week results from a phase II trial. *Journal of the American Academy of Dermatology* Vol.60, Ab.168, San Francisco, 67th Annual Meeting of the

TNF-blockade therapy: a review and analysis of 127 cases. *Journal of Dermatological*

Gerdes, S. & Mrowietz, U. (2009). Impact of comorbidities on the management of psoriasis.

Gisondi, P., Gubinelli, E., Cocuroccia, B. & Girolomoni, G. (2004). Targeting tumor necrosis

Gladman, D.D., Mease, P.J., Ritchlin, C.T., Choy, E.H., Sharp, J.T., Ory, P.A., Perdok, R.J. &

Golant, A.K. & Guttman-Yassky, B.S.E. (2011). Psoriasis Treatments: A review of the current

Gordon, K.B., Gottlieb, A.B., Leonardi, C.L., Elewski, B.E., Wang, A., Jahreis, A. & Zitnik, R.

Gordon, K.B., Langley, R.G., Leonardi, C., Toth, D., Menter, M.A., Kang, S., Heffernan, M.,

Gottlieb, A.B., Krueger, J.G., Wittkowski, K., Dedrick, R., Walicke, P.A. & Garovoy, M.

Gottlieb A.B., Matheson, R.T., Lowe, N., Krueger, G.G., Kang, S., Goffe, B.S., Gaspari, A.A.,

Gottlieb, A.B., Evans, R., Li, S., Dooley, L.T., Guzzo, C.A., Baker, D., Bala, M., Marano, C.W.

Gottlieb, A., Menter, A., Mendelsohn, A., Shen, Y.K., Li, S., Guzzo, C., Fretzin, S., Kunynetz,

Griffiths, C.E., Strober, B.E., van de Kerkhof, P., Ho, V., Fidelus-Gort, R., Yeilding, N.,

Heiberg, M.S., Koldingsnes, W., Mikkelsen, K., Rødevand, E., Kaufmann, C., Mowinckel, P.

psoriasis. *New England Journal of Medicine,* Vol.362, No.2, pp.118-128. Haraoui, B., Cameron, L., Ouellet, M. & White, B. (2006). Anti-infliximab antibodies in

antibody. *Archives of Dermatology*, Vol.138, No.5, pp. 591-600.

*Dermatology,* Vol.139, No.12, pp.1627-1632.

*Academy of Dermatology,* Vol.51, No.4, pp.534-542.

crossover trial. *The Lancet,* Vol.373, No.9664, pp.633-640.

factor-alpha in the therapy of psoriasis. *Current Drug Targets - Inflammation &*

Sasso, E.H. (2007). Adalimumab for long-term treatment of psoriatic arthritis: fortyeight week data from the adalimumab effectiveness in psoriatic arthritis trial.

(2006a). Clinical response in psoriasis patients discontinued from and then reinitiated on Etanercept therapy*. Journal of Dermatological Treatment,* Vol.17, No.1,

Miller, B., Hamlin, R., Lim, L., Zhong, J., Hoffman, R. & Okun, M.M. (2006b). Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. *Journal of American Academy of Dermatology,* Vol.55, No.4, pp.598-606.

(2002). Psoriasis as a model for T-cell-mediated disease: immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-CD11a

Ling, M., Weinstein, G.D., Nayak, A., Gordon, K.B. & Zitnik, R. (2003). A randomized trial of etanercept as monotherapy for psoriasis. *Archives of*

& Menter, A. (2004). Infliximab induction and maintenance therapy for moderateto-severe psoriasis: a phase III, multicenter, double-blind trial. *Journal of American*

R. & Kavanaugh, A. (2009). Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled,

Guzzo, C., Xia, Y., Zhou, B., Li, S., Dooley, L.T., Goldstein, N.H. & Menter, A. (2010). Comparison of ustekinumab and etanercept for moderate-to-severe

patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response. *Journal of Rheumatology,* Vol.33, No.1, pp.31-

& Kvien, T.K. (2008). The comparative one-year performance of anti-tumor necrosis

*Current Problems in Dermatology*, Vol.38, pp.21-36.

*Arthritis & Rheumatism,* Vol.56, No.2, pp.476-488.

research pipeline. *Psoriasis Forum,* Vol.17, No.1, pp.11-23.

*Allergy,* Vol.3, No.2, pp.175-183.

pp. 9-17.

36.

factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study. *Arthritis and Rheumatism,* Vol.59, No.2, pp.234-240.

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 351

Lowes, M.A., Chamian, F., Abello, M.V., Fuentes-Duculan, J., Lin, S.L., Nussbaum, R.,

Lowes, M.A., Kikuchi, T., Fuentes-Duculan, J., Cardinale, I., Zaba, L.C., Haider, A.S.,

Malaviya, R., Sun, Y., Tan, J.K., Wang, A., Magliocco, M., Yao, M., Krueger, J.G. & Gottlieb,

Mease, P.J., Goffe, B.S., Metz, J., VanderStoep, A., Finck, B. & Burge, D.J. (2000). Etanercept

Mease, P.J., Kivitz, A.J., Burch, F.X., Siegel, E.L., Cohen, S.B., Ory, P., Salonen, D.,

Mease, P.J., Gladmanm D.D., Ritchlinm C.T., Rudermanm E.M., Steinfeldm S.D., Choy, E.H.,

Mease, P.J., Ory, P., Sharp, J.T., Ritchlin, C.T., Van den Bosch, F., Wellborne, F., Birbara, C.,

Mease, P.J. & Reich, K. (2009). Alefacept with methotrexate for treatment of psoriatic

study. *Journal of American Academy of Dermatology,* Vol.60, No.3, pp.402-411. Mease, P.J., Woolley, J.M., Singh, A., Tsuji, W., Dunn, M. & Chiou, C.F. (2010). Patient-

Mease, P., Genovese, M.C., Gladstein, G., Kivitz, A.J., Ritchlin, C., Tak, P.P., Wollenhaupt, J.,

19057-19062.

Vol.128, No.5, pp.1207-1211.

Vol.55, No.4, pp.590-597.

Vol.356, No.9227, pp.385-390.

Vol.50, No.7, pp.2264-2272.

Vol.52, No.10, pp.3279-3289.

*Rheumatic Diseases,* Vol.68, No.5, pp.702-709.

*Journal of Rheumatology,* Vol.37, No.6, pp.1221-1227.

*and Rheumatism,* Vol. 63, No.4, pp.939-948.

Novitskaya, I., Carbonaro, H., Cardinale, I., Kikuchi, T., Gilleaudeau, P., Sullivan-Whalen, M., Wittkowski, K.M., Papp, K., Garovoy, M., Dummer, W., Steinman, R.M. & Krueger, J.G. (2005). Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). *Proceedings of the National Academy of Sciences*, Vol.102, No.52, pp.

Bowman, E.P. & Krueger, J.G. (2008). Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. *The Journal of Investigative Dermatology,*

A.B. (2006). Etanercept induces apoptosis of dermal dendritic cells in psoriatic plaques of responding patients. *Journal of the American Academy of Dermatology,*

in the treatment of psoriatic arthritis and psoriasis: a randomised trial. *The Lancet,*

Rubenstein, J., Sharp, J.T. & Tsuji, W. (2004). Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. *Arthritis & Rheumatism,*

Sharp, J.T., Ory, P.A., Perdok, R.J. & Weinberg, M.A. (2005). Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. *Arthritis & Rheumatism,*

Thomson, G.T., Perdok, R.J., Medich, J., Wong, R.L. & Gladman, D.D. (2009). Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT). *Annals of the*

arthritis: open-label extension of a randomized, double-blind, placebo-controlled

reported outcomes in a randomized trial of etanercept in psoriatic arthritis. *The*

Bahary, O., Becker, J.C., Kelly, S., Sigal, L., Teng, J. & Gladman, D. (2011). Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. *Arthritis*

Kothary, N., Diak, I.L., Brinker, A., Bezabeh, S., Avigan, M. & Pan, G.D. (2011). Progressive

Kraan, M.C., van Kuijk, A.W., Dinant, H.J., Goedkoop, A.Y., Smeets, T.J., de Rie, M.A.,

Krueger, G.G. (2002). Selective targeting of T cell subsets: focus on alefacept - a remittive therapy for psoriasis. *Expert Opinion on Biological Therapy,* Vol.2, No.4, pp.431-441. Krueger, G.G., Papp, K.A., Stough, D.B., Loven, K.H., Gulliver, W.P. & Ellis, C.N. (2002). A

Krueger, G.G., Gottlieb, A.B., Sterry, W., Korman, N. & Van De Kerkhof, P. (2008). A

psoriasis. *The Journal of Dermatological Treatment,* Vol.19, No.3, pp.146-155. Kunz M. (2009). Current treatment of psoriasis with biologics. *Current Drug Discovery*

Kurzeja, M., Rudnicka, L. & Olszewska, M. (2011). New interleukin-23 pathway inhibitors in

Lebwohl, M., Christophers, E., Langley, R., Ortonne, J.P., Roberts, J. & Griffiths, C.E. (2003).

Leman, J. & Burden, A. (2008). Treatment of severe psoriasis with infliximab. *Journal of Therapeutics and Clinical Risk Management,* Vol.4, No.6, pp.1165-1175. Leonardi, C.L., Powers, J.L., Matheson, R.T., Goffe, B.S., Zitnik, R., Wang, A. & Gottlieb, A.B.

Leonardi, C.L., Kimball, A.B., Papp, K.A., Yeilding, N., Guzzo, C., Wang, Y., Li, S., Dooley,

Leonardi, C., Strober, B., Gottlieb, A.B., Elewski, B.E., Ortonne, J.P., van de Kerkhof, P.,

*Journal of American Academy of Dermatology,* Vol.47, No.6, pp.821-833. Krueger, G.G., Langley, R.G., Leonardi, C., Yeilding, N., Guzzo, C., Wang, Y., Dooley, L.T. &

patients. *Journal of American Academy of Dermatology*, 21 April.

*Arthritis & Rheumatism,* Vol.46, No.10, pp.2776-2784.

*Technologies,* Vol.6, No.4, pp.231-240.

*Dermatology,* Vol.139, No.6, pp.719-727.

*Lancet,* Vol.371, No.9625, pp.1665-1674.

*Dermatology,* Vol.9, No.8, pp.928-937.

*Journal of Medicine,* Vol.349, No.21, pp.2014-2022.

Vol.12, No.2, pp.113-125*.*

592.

multifocal leukoencephalopathy associated with efalizumab use in psoriasis

Dijkmans, B.A., Vaishnaw, A.K., Bos, J.D. & Tak, P.P. (2002). Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis.

randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis.

Lebwohl, M. (2007). A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. *The New England Journal of Medicine,* Vol.356, No.6, pp.580-

multicenter, open-label study of repeat courses of intramuscular alefacept in combination with other psoriasis therapies in patients with chronic plaque

dermatology: ustekinumab, briakinumab, and secukinumab. *Am J Clin Dermatol.*

An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. *Archives of*

(2003). Etanercept as monotherapy in patients with psoriasis. *The New England*

L.T. & Gordon, K.B. (2008). Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). *The*

Chiou, C.F., Dunn, M. & Jahreis, A. (2010). Long-term safety and efficacy of etanercept in patients with psoriasis: an open-label study. *Journal of Drugs in*

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 353

*Journal of the American Academy of Dermatology,* Vol.57, No.2, pp.269-275. Papp, K., Tyring, S., Lahfa, M., Prinz, J., Griffiths, CE., Nakanishi, A.M., Zitnik, R., van de

Papp, K.A., Caro, I., Leung, H.M., Garovoy, M. & Mease, P.J. (2007). Efalizumab for the

Papp, K.A., Langley, R.G., Lebwohl, M., Krueger, G.G., Szapary, P., Yeilding, N., Guzzo, C.,

Papp, K., Crowley, J., Ortonne, J.P., Leu, J., Okun, M., Gupta, S.R., Gu, Y. & Langley, R.G.

Pfizer. (January, 2010). Pfizer pipeline. In: *www.pfizer.com,* 16.05.2011*,* available from: *http://www.pfizer.com/files/research/pipeline/2010\_0127/pipeline\_2010\_0127.pdf*. Piccolo, D., Di Cesare, A., Fargnoli, M.C., Paolini, M., Vecchiotti, S. & Peris, K. (2008).

Raho, G., Vena, G.A., Bizzoca, A., Cassano, N., Garofalo, E., Congedo, M. & Gennarini, G.

Reich, K., Nestle, F.O., Papp, K., Ortonne, J.P., Evans, R., Guzzo, C., Li, S., Dooley, L.T. &

Reich, K., Nestle, F.O., Papp, K., Ortonne, J.P., Wu, Y., Bala, M., Evans, R., Guzzo, C., Li, S.,

Reich, K., Ortonne, J.P., Kerkmann, U., Wang, Y., Saurat, J.H., Papp, K., Langley, R. &

Revicki, D., Willian, M.K., Saurat, J.H., Papp, K.A., Ortonne, J.P., Sexton, C. & Camez, A.

*Immunopharmacology and Immunotoxicology,* Vol.33, No.1, pp.227-231. Ramos-Casals, M., Brito-Zerón, P., Soto, M.J., Cuadrado, M.J. & Khamashta, M.A. (2008).

trial (PHOENIX 2). *The Lancet,* Vol.371, No.9625, pp.1675-1684.

*The British Journal of Dermatology,* Vol.164, No.2, pp.434-441.

*European Journal of Dermatology,* Vol.18, No.4, pp.459-482.

*Clinical Rheumatology,* Vol.22, No.5, pp.847-861.

Trial. *Dermatology,* Vol.221, No.2, pp.172-178.

No.9494, pp.1367-1374.

pp.1161-1168.

*Journal of Dermatology,* Vol.152, No.6, pp.1304-1312.

No.2, pp.57-66.

arthritis: an open-label study in 30 patients previously treated with other biologics.

Kerkhof, P.C. & Melvin, L. (2005). A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. *The British*

treatment of psoriatic arthritis. *Journal of Cutaneous Medicine and Surgery*, Vol.11,

Hsu, M.C., Wang, Y., Li, S., Dooley, L.T. & Reich, K. (2008). Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled

(2011). Adalimumab for moderate to severe chronic plaque psoriasis: efficacy and safety of retreatment and disease recurrence following withdrawal from therapy.

Effective control of psoriasis by etanercept in a patient with HCV-related diseases.

(2010). Influence of infliximab on keratinocyte apoptosis in psoriasis patients.

Autoimmune diseases induced by TNF-targeted therapies. *Best Practice & Research*

Griffiths, C.E. (2005). Infliximab induction and maintenance therapy for moderateto-severe psoriasis: a phase III, multicentre, double-blind trial. *The Lancet,* Vol.366,

Dooley, L.T. & Griffiths, C.E. (2006). Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial. *The British Journal of Dermatology,* Vol.154, No.6,

Griffiths, C.E. (2010). Skin and nail responses after 1 year of infliximab therapy in patients with moderate-to-severe psoriasis: a retrospective analysis of the EXPRESS

(2008). Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in

Menter, A., Cather, J.C., Baker, D., Farber, H.F., Lebwohl, M. & Darif, M. (2006). The efficacy

psoriasis. *Journal of American Academy of Dermatology,* Vol.54, No.1, pp.61-63. Menter, A., Feldman, S.R., Weinstein, G.D., Papp, K., Evans, R., Guzzo, C., Li, S., Dooley,

Menter, A., Tyring, S.K., Gordon, K., Kimball, A.B., Leonardi, C.L., Langley, R.G., Strober,

Menter, A., Augustin, M., Signorovitch, J., Yu, A.P., Wu, E.Q., Gupta, S.R., Bao, Y. & Mulani,

Montané, E., Sallés, M., Barriocanal, A., Riera, E., Costa, J. & Tena, X. (2007). Antitumor

Nestle, F.O., Kaplan, D.H. & Barker, J. (2009). Psoriasis. *New England Journal of Medicine,*

Nograles, K.E., Brasington, R.D. & Bowcock, A.M. (2009). New insights into the

Novartis. (July, 2010). Research and development: clinical pipeline. In: *www.novartis.com,*

Ortonne, J.P., Reich, K., Sterry, W. & Terpstra, I. (2008a). Safety and efficacy (PASI 90 and

Meeting of the American Academy of Dermatology (AAD), February 1-5. Paller, A.S., Siegfried, E.C., Langley, R.G., Gottlieb, A.B., Pariser, D., Landells, I., Hebert,

Paller, A.S., Siegfried, E.C., Eichenfield, L.F., Pariser, D., Langley, R.G., Creamer, K. &

*American Academy of Dermatology,* Vol.58, No.1, pp.106-115.

rechallenges. *Clinical Rheumatology,* Vol.26, No.9, pp.1527-1529.

*events/pipeline-update/2010/2010-11-17-making-science\_happen.pdf*.

*Academy of Dermatology,* Vol.62, No.5, pp.812-818.

Vol.56, No.1, pp.31.e1-15.

Vol.361, No.5, pp.496-509.

*Rheumatology,* Vol.5, No.2, pp.83-91.

*of Medicine,* Vol.358, No.3, pp.241-251.

of multiple courses of alefacept in patients with moderate to severe chronic plaque

L.T., Arnold, C. & Gottlieb, A.B. (2007). A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. *Journal of American Academy of Dermatology,*

B.E., Kaul, M., Gu, Y., Okun, M. & Papp, K. (2008). Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. *Journal of*

P. (2010). The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. *Journal of American*

necrosis factor-induced neutropenia: a case report with double positive

pathogenesis and genetics of psoriatic arthritis. *Nature Clinical Practice*

16.05.2011*,* available from: *http://www.novartis.com/downloads/investors/presentations-*

global evaluation) of subcutaneous certolizumab pegol in patients with moderate to severe chronic plaque psoriasis: results from a doubleblind, placebo-controlled trial. *Journal of the American Academy of Dermatology,* Vol.58, Ab.4, San Antonio, 66th Annual Meeting of the American Academy of Dermatology (AAD), February 1-5. Ortonne, J.P., Reich, K. & Keininger, D.L. (2008b). Certolizumab pegol improved health-

related quality of life in patients with psoriasis: data from a phase II study. *Journal of the American Academy of Dermatology,* Vol.58, Ab.121, San Antonio, 66th Annual

A.A., Eichenfield, L.F., Patel, V., Creamer, K. & Jahreis, A. (2008). Etanercept treatment for children and adolescents with plaque psoriasis. *New England Journal*

Kricorian, G. (2010). Long-term etanercept in pediatric patients with plaque psoriasis. *Journal of the American Academy of Dermatology,* Vol.63, No.5, pp.762-768. Papoutsaki, M., Chimenti, M.S., Costanzo, A., Talamonti, M., Zangrilli, A., Giunta, A.,

Bianchi, L. & Chimenti, S. (2007). Adalimumab for severe psoriasis and psoriatic

arthritis: an open-label study in 30 patients previously treated with other biologics. *Journal of the American Academy of Dermatology,* Vol.57, No.2, pp.269-275.

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 355

Toichi, E., Torres, G., McCormick, T.S., Chang, T., Mascelli, M.A., Kauffman, C.L., Aria, N.,

Tyring, S., Gordon, K.B., Poulin, Y., Langley, R.G., Gottlieb, A.B., Dunn, M. & Jahreis, A.

patients with psoriasis. *Archives of Dermatology,* Vol.143, No.6, pp.719-726. UCB, Inc. (December, 2010). Cimzia package insert. In: *www.cimzia.com,* 28.05.2011*,* available

Vaishnaw, A.K. & TenHoor, C.N. (2002). Pharmacokinetics, biologic activity, and tolerability

van de Kerkhof, P.C., Segaert, S., Lahfa, M., Luger, T.A., Karolyi, Z., Kaszuba, A., Leigheb,

van Eden, W. (2008). XToll, a recombinant chaperonin 10 as an anti-inflammatory

van, L., Modi, S.V., Yang, D.J. & Hsu, S. (2008). Sustained efficacy and safety of adalimumab

Vena, G.A. & Cassano, N. (2007). Anti-tumor necrosis factor therapies for psoriasis. *Expert*

Weger, W. (2010). Current status and new developments in the treatment of psoriasis and

Williams, B., Vanags, D., Hall, S., McCormack, C., Foley, P., Weiss, J., Johnson, B., Latz, E. &

Yawalkar, N., Tscharner, G.G., Hunger, R.E. & Hassan, A.S. (2009). Increased expression of

Zaba, L.C., Cardinale, I., Gilleaudeau, P., Sullivan-Whalen, M., Suárez-Fariñas, M., Fuentes-

psoriasis. *Journal of Dermatological Science,* Vol.54, No.2, pp.99-105.

*Pharmacokinetics and Pharmacodynamics,* Vol.29, No.5-6, pp.415-426.

immunity. *Nature Reviews. Immunology,* Vol.3, No.2, pp.133-146.

*from: http://www.cimzia.com/pdf/Prescribing\_Information.pdf.*

Vol.159, No.5, pp.1177-1185.

*Review of Dermatology,* Vol.2, pp.335-349.

*Dermatology,* Vol. 144, No.5, pp.683-685.

533.

pp.804-806.

No.4, pp.810-20.

pp.3183-3194.

Gottlieb, A.B., Everitt, D.E., Frederick, B., Pendley, C.E. & Cooper, K.D. (2006). An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. *The Journal of Immunology,* Vol.177, No.7, pp.4917-4926. Trinchieri, G. (2003). Interleukin-12 and the regulation of innate resistance and adaptive

(2007). Long-term safety and efficacy of 50 mg of etanercept twice weekly in

of alefacept by intravenous and intramuscular administration. *Journal of*

G., Camacho, F.M., Forsea, D., Zang, C., Boussuge, M.P., Paolozzi, L. & Wajdula, J. (2008). Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension. *The British Journal of Dermatology,*

immunomodulator. *Current Opinion in Investigational Drugs,* Vol. 9, No.5, pp.523-

in psoriasis treatment: a retrospective study of 49 patients with and without a history of TNF-alpha antagonist treatment. *Archives of Dermatology,* Vol.144, No.6,

psoriatic arthritis with biological agents. *The British Journal of Pharmacology*, Vol.160,

Feeney, D. (2008). Efficacy and safety of chaperonin 10 in patients with moderate to severe plaque psoriasis: evidence of utility beyond a single indication. *Archives of*

IL-12p70 and IL-23 by multiple dendritic cell and macrophage subsets in plaque

Duculan, J., Novitskaya, I., Khatcherian, A., Bluth, M.J., Lowes, M.A. & Krueger, J.G. (2007). Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. *The Journal of Experimental Medicine,* Vol.204, No.13,

patients with moderate to severe plaque psoriasis. *The British Journal of Dermatology,*  Vol.158, No.3, pp.549-557.

Roberts, L. & McColl, G.J. (2004). Tumour necrosis factor inhibitors: risks and benefits in

Roberts, J.L., Ortonne, J.P., Tan, J.K., Jaracz, E. & Frankel, E. (2010). The safety profile and

Russell, C.B., Kerkhof, K., Bigler, J., Timour, M., Welcher, A.A., Novitskaya, I., Khatcherian,

Saougou, I., Markatseli, T.E., Papagoras, C., Voulgari, P.V., Alamanos, Y. & Drosos, A.A.

Saurat, J.H., Stingl, G., Dubertret, L., Papp, K., Langley, R.G., Ortonne, J.P., Unnebrink, K.,

Scallon, B.J., Moore, M.A., Trinh, H., Knight, D.M. & Ghrayeb, J. (1995). Chimeric anti-TNF-

Shikiar, R., Heffernan, M., Langley, R.G., Willian, M.K., Okun, M.M. & Revicki, D.A. (2007).

Sterry, W., Ortonne, J.P., Kirkham, B., Brocq, O., Robertson, D., Pedersen, R.D., Estojak, J.,

Swedish Medical Center (September, 2009). Rituxan With or Without Methotrexate in

Thaçi, D., Ortonne, J.P., Chimenti, S., Ghislain, P.D., Arenberger, P., Kragballe, K., Saurat,

activates immune effector functions. C*ytokine,* Vol.7, No.3, pp.251-259. Schottelius, A.J., Moldawer, L.L., Dinarello, C.A., Asadullah, K., Sterry, W. & Edwards, C.K.

trial. *Journal of Dermatological Treatment,* Vol.18, No.1, pp.25-31.

*The British Journal of Dermatology,* Vol.163, No.2, pp.402-411.

Vol.158, No.3, pp.549-557.

*Dermatology,* Vol.62, No.6, pp.968-978.

*Arthritis and Rheumatism,* Vol.40, No.5, pp.398-406.

*Experimental Dermatology*, Vol.13, No.4, pp.193-222.

*http://clinicaltrials.gov/ct2/show/NCT00509678*.

*Dermatology,* Vol.130, No.S1, S46.

No.3, pp.558-566.

693.

patients with moderate to severe plaque psoriasis. *The British Journal of Dermatology,*

patients with rheumatoid arthritis. *Internal Medicine Journal,* Vol.34, No.12, pp.687-

sustained remission associated with response to multiple courses of intramuscular alefacept for treatment of chronic plaque psoriasis. *Journal of American Academy of*

A., Krueger, J., Rand, H., Martin, D.A. & Zeichner, J.A. (2010). Blockade of IL-17R with AMG 827 leads to rapid reversal of gene expression. *Journal of Investigative*

(2011). Sustained Clinical Response in Psoriatic Arthritis Patients Treated with Anti-TNF Agents: A 5-year Open-Label Observational Cohort Study. *Seminars in*

Kaul, M. & Camez, A. (2008). Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). *The British Journal of Dermatology,* Vol.158,

alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and

3rd. (2004). Biology of tumor necrosis factor-alpha- implications for psoriasis.

Adalimumab treatment is associated with improvement in health-related quality of life in psoriasis: patient-reported outcomes from a phase II randomized controlled

Molta, C.T. & Freundlich, B. (2010). Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis: PRESTA randomised double blind multicentre trial. *The British Medical Journal,* Feb 2; 340:c147. doi: 10.1136/bmj.c147.

Psoriatic Arthritis. In: *www.clinicaltrials.gov,* 16.05.2011*,* available from:

J.H., Khemis, A., Sprøgel, P., Esslinger, H.U., Unnebrink, K. & Kupper, H. (2010). A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study.

**17**

*Brazil*

**Food, Nutrition and Diet Therapy in Psoriasis**

Diet has been suggested to play a role in the etiology and pathogenesis of psoriasis (Araujo et al., 2009; Wolters, 2005). Periods of fasting, a hypocaloric and vegetarian diet have been associated with an improvement in symptoms due to changes in the metabolism of polyunsaturated fatty acids (PUFAs) and an influence on the profile of eicosanoids, leading to suppression of the inflammatory process (Lithell et al., 1983; Rucevic et al., 2003; Wolters, 2005). The consumption of alcoholic beverages is prevalent among patients with psoriasis and is the greatest cause of the high mortality rate among individuals with moderate to severe forms of the disease and should therefore be avoided (Chistophers, 2001; Poikolainen et al., 1990; Smith & Fenske, 2000; Wolters, 2005). According to several authors, calcitriol (the active form of vitamin D) and its analogs have anti-proliferation, pro-differentiation and immune-regulating properties that may inhibit the growth and maturation of keratinocytes, with oral supplementation often suggested for patients who do not topically use calcitriol

The skin acts as an interface between the body and surrounding environment, thus the skin is constantly exposed to both endogenous and exogenous pro-oxidants, leading to the generation of harmful oxidant species. Oxidative stress and the generation of excessive free radicals have been related to skin inflammation in psoriasis. Patients with this condition have reduced plasma levels of β-carotene and α-tocopherol as well as a decline in serum selenium and high concentrations of malondialdehyde, which is a marker of lipid peroxidation in the plasma and red blood cells (Briganti & Picardo, 2003; Azzini et al., 1995;

Data from literature indicates that the topical application or oral administration of antioxidants is suggested as preventive therapy for the natural aging of the skin and cancer caused by ultraviolet rays (Briganti & Picardo, 2003). With regard to lipids, studies have demonstrated the anti-inflammatory effect of fish oil in individuals with psoriasis, as diets rich in omega 3 modify the metabolism of PUFAs, thereby influencing the profile of eicosanoids, which leads to the suppression of the inflammatory process (Smith & Fenske, 2000). A number of authors report an association between latent sensitivity to gluten (preceliac disease state) and different skin diseases, including psoriasis, suggesting a gluten-free diet may provide beneficial effects (Duggan, 2004; Humbert et al., 2006; Leffler et al., 2003;

**1. Introduction**

Serwin et al., 2003).

(Andorini, 2002; Holick, 2003; Wolters, 2005).

Michaelsson et al., 2003; Nelson, 2002; Wolters, 2005).

Maria Lucia Diniz Araujo, Paulla Suylane Santos Fernandes Costa

and Maria Goretti Pessoa de Araujo Burgos

*Federal University of the Pernambuco*

Zeinn, N.N. & Etanercept Study Group. (2005). Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. *Journal of Hepatology,*  Vol.42, No.3, pp.315-322.


**2. Reservoir stimulation strategies**

Reservoir stimulation is simply described as the induction of formations to improve hydrocarbon production. This is can be accomplished by repairing the formation damage, especially at the vicinity of the wellbore, and/or changing the natural state of the rock or fluids to increase reservoir productivity. The advent in oil and gas production from unconventional reserves has given rise to the development of several stimulation approaches. This inventory (of methods) has expanded over the years, with considerable improvements made to boost the effectiveness and efficiency of a sizeable number of them. Some techniques are focused on repairing damages that have impaired the conductivity of rocks surrounding the wellbore, and some artificially create additional channels to enable easy flow of reservoir fluids towards the wellbore, while others alter the properties of reservoir fluids to make them less adhesive to host rocks and to encourage nonviscous-like fluid flow into wellbores. Numerous stimulation techniques are currently employed in

*Introductory Chapter: Developments in the Exploitation of Unconventional Hydrocarbon… DOI: http://dx.doi.org/10.5772/intechopen.86625*

practice. These include hydraulic fracturing, surfactant flooding and treatment, water imbibition, acidisation, thermal stimulation and treatment and electrokinetics potential.


**2.6 Blackspot disease**

170 Fungicides for Plant and Animal Diseases

Generally, the gray mold disease appears as a gray to brown mold on dying plant tissue such as spent flowers, leaves and stems (Figure 2 A, B). The symptoms are observed as light spot surrounded by maroon halos on petals. These spots enlarge and turn brown over time. Infected petals may fall off. Cankers and dieback may be observed on stems. A wide range of plant varieties are affected by this disease. Susceptible plant species to gray mold include house plants such as African violets, amaryllis, Amazon-lily, azaleas, begonias, cacti, caladium, calla lily, camellias, castorbeans, chrysanthemums, cinerarias, coleus, corn flowers, dalias, dracaenas, dusty millers, ferns, fig, fuchsias, ardenias, gloxinias, heliotrope, orchids, passion flower, and poinsettias. In addition, members of herbaceous annual plants susceptible to gray mold are ageratum, begonia, caldium, carnation, celosia, chicory, geranium, gerbera, gladiola, impatiens, marigold, nasturtium, pansy, petunia, snapdragon, statice, stock, sunflower, sweet pea, verbena, and zinnia. Furthermore herbaceous perennials including anemone, aster, baby's-breath, bellflower, bleeding heart, bloodroot, bluebell, buttercup, calendula, candytuft, carnation, chrysanthemum, chicory, coralberry, cranesbill, dandelion, daylily, delphinium, Dutchman's- pipe, foxglove, globe-amaranth, hyacinth, iris, Jack-in-the-pulpit, liy, lily-of-the-valley, lupine, Maltese cross, narcissus, peony, phlox, pinks, plantain lily, poppy, primrose, purple coneflower, rose, snowdrop,

Fig. 2. Disease symptom of Gray mold disease on red raspberry fruit (A) and on tomato fruit

Gray mold disease is caused by many strains of the fungus *Botrytis cinerea*. This fungus is not host specific and therefore infects many different types of plant species. Symptoms vary with the plant species attacked. The fungus needs moisture to cause infection and a

To contain the disease all infected tissue should be remove as soon as possible; infected debris should be collected. The plants should be well spaced and weeded to allow good air circulation; sprinkler irrigation and wetting of the foliage should be avoided because this provides the humidity needed for the proliferation of the disease. Application of fungicides

tulip, vinca, and violet are susceptible to gray mold disease.

(B). Photo, courtesy of P. R. Bristout.

**2.5.1 Control of gray mold disease**

**2.5 Life cycle of gray mold causal agents**

favorable temperature ranging from 18° C to 25° C.

**2.4 Gray mold disease**

Blackspot is a disease of roses. It appears as small black spots on the upper surface of the leaves (Figure 3 A), which first appear on the lowest leaves and may first appear as purple spots on stems that eventually turn black. The area around the spots turns yellow and the spot may coalesce to form black blotches (Figure 3 A, B, C). The yellow leaves easily fall off the plants. The disease spreads from lower leaves to younger upper leaves leading to further defoliation. Severe defoliation reduces vigor of the plants and decrease flower production (Gachomo et al., 2010).

Fig. 3. Photographs of rose leaves infected with *Diplocarpon rosae* showing, (A) the symptoms on leaves followed by the yellowing of the leaves (B) a close up of a sporulating spot showing the dome shaped-unopened acervuli that have pushed the cuticle upwards, (C) a close up of a sporulating spot where a mass of white conidia oozes out of the acervuli (Adopted from Gachomo, et al., 2010)

#### **2.6.1 Life cycle of blackspot causal agents**

Blackspot disease is caused by a fungal pathogen, *Diplocarpon rosae*. The fungus overwinters on infected canes and fallen debris (Gachomo, 2005). During the favorable weather conditions the spores are splashed from infected plant parts to young leaves by rain splash and irrigation water. The fungus produces conidia within 10 to 14 days (Figure 4 A, B) which are splashed to other young leaves. Several disease cycles can occur within a growing season. Once established the disease is difficult to control.

Control of Major Diseases in Horticulture 173

Bottom rot disease of lettuce can be recognized by brown spots that initially appear on the midribs of the lower leaves that are in contact with the soil (Figure 5 A). The rot spreads rapidly under favorable conditions to affect larger sections of the midrib and leaf blades, and may affect the inner leaves of the head. Symptoms are more severe during

Fig. 5. Disease symptom of bottom rot (A) and Fusarium wilt of lettuce (B). Photos courtesy

Bottom rot is caused by a soilborne fungal pathogen *Rhizoctonia solani*. The fungus overwinters in the soil or in crop debris as sclerotia or mycelia. It may survive in alternate hosts and serve as a source of inoculum, sexual spores. It is disseminated by wind or rain splash in the next growing season. *R. Solani* has a wide host range e.g. eggplant, soybean,

Cultural measures includes three year rotations with non-host plants; collecting plant debris and burying it or plowing it deep in the soil; planting varieties that have an upright architecture to reduce contact with the soil; keeping the fields weed free and removing volunteer crops to reduce possible alternate hosts. Since *R. Solani* is able to survive on non decomposed organic matter, it is important to avoid planting lettuce in a field that has high amounts of organic matter that is not decomposed; avoid overhead irrigation during heading of the plants; plant lettuce on ridges which increases aeration and helps avoid plants contact with the soil. Fungicides (Table 2) are the most effective means to control bottom rot disease. However, fungicide control is only satisfactory when used in combination with cultural control strategies. Proper placement and timing of fungicide

**3. Diseases of vegetables**

heading.

**3.1 Bottom rot disease of lettuce**

of A. F. Sherf (A) and T. A. Zitter (B).

**3.1.2 Control of bottom rot disease**

**3.1.1 Fungal agent of bottom rot disease**

potato, cotton, alfafa, maize, wheat and several weed species.

applications are key elements for effective disease management.

Fig. 4. Light microscope photographs of *Diplocarpon rosae* growing on artificial malt agar medium: (A) *D. rosae* two-celled conidial structures before and during germination. (B) Three day-old conidium germination. (Courtesy of E. W. Gachomo).

#### **2.6.2 Control of blackspot disease**

Control practices start with planting resistant rose varieties where available. Good sanitation is key to keeping the rose disease free. Recommended cultural practices are: All infected debris should be collected and burnt or buried; all infected canes must be pruned; overhead irrigation must be avoided because it tends to splash conidia from infected to non-infected parts of the plants. It recommended to water plants at the base; the plants should be preferably watered in the morning as opposed to the evening, because the conidia require several hours of wetness to cause infection, therefore watering in the morning reduces the hours of leaf wetness. In addition, plants should be well spaced and kept weed free to allow for aeration. Furthermore, one must avoid planting susceptible plants under the shade. When blackspot disease is establish, its control relies heavily on fungicides. In Table 1, the fungicides recommended in blacksopt disease management are listed.

\*FRAC (Fungicides Resistance Action Committee)

Table 1. Fungicides labeled for the control of powdery mildew on roses.


**1. Introduction**

Climate change caused by increasing atmospheric carbon dioxide (CO2) concentrations has been extensively studied in the context of global warming, and the land carbon cycle feedback is recognized as one of the biggest sources of uncertainty in climate projection [1]. Global warming is proceeding with a greening trend of the Earth, as shown by satellite and ground observations of increases in leaf area index [2,3], canopy cover [4], and biomass [5]. A greening Earth has significant consequences for the terrestrial carbon sink, the integrity of ecosystem, and climate [6,7]. Numerous mechanisms appear to underlie the observed greening, including changes in the climate system [8,9]. Among the mechanisms supporting the greening Earth, CO2 fertilization is considered the dominant factor in enhancing vegetation, with evidence from free-air CO2 enrich (FACE) experiments [10], satellite observations [2,4], and ground observations [11]. Climate change is also substantially contributing to the increase in global vegetation productivity because of the indirect effect of increasing CO2 concentrations [9]. For instance, global warming is enhancing vegetation growth in high latitudes [12,13]. As such, each mechanism contributing to vegetation growth has been scrutinized independently, but, in contrast to climate change studies, the global factors affecting vegetation response have not been well studied and summarized. Therefore, the combination and interactions of multiple different climatological and biophysical mechanisms make it difficult to predict the future growth of vegetation at the global scale. As a result, the big discrepancy between modeled and observed sensitivity to CO2 concentrations is always a source of controversy in the prediction of the future carbon cycle [14]. If climate constrains increase, climate change can cancel the positive effects of CO2 or of other biogeochemical fertilization (e.g. nitrogen deposition) on vegetation, and possibly accelerate global warming. Therefore, understanding the relative strength of climate variables or increasing CO2 concentrations, leading to greening or browning of the Earth, is imperative for future projections.

We firstly summarized and analyzed the trends in climate and vegetation responding to increasing CO2 concentrations from the subset of the Coupled Model Intercomparison Project Phase 5 (CMIP5). The CMIP5 dataset includes present run and future projection data produced by Earth system models following several experimental scenarios. Future vegetation growth depends on the type, magnitude, and seasonal timing of climatic changes and their interactions with vegetation physiology. To simplify the understanding of these complex mechanisms, we divided the vegetated areas into three categories, namely temperature-limited, water-limited, and radiation-limited areas, following Nemani et al. [9].

Then, we decomposed the mechanisms enhancing vegetation growth into three factors: CO2 concentration fertilization effect, radiative climate change, and local climate feedback by vegetation growth. By assessing these three factors quantitatively, we can answer the question as to whether increasing CO2 concentrations will tighten or relax climate constrains on vegetation at the global scale. Friedlingstein et al. [1] evaluated the strengths of the effects of CO2 fertilization and temperature increase on land vegetation carbon storage. Lemordant et al. [15] decomposed the climate effects on evapotranspiration into net radiation, precipitation, and vapor pressure deficit (VPD). However, none of them counted the local climate feedback effect at the global scale. Therefore, contradicting results of vegetation growth by different mechanisms made future predictions confusing. For instance, it is hard to discuss the regional trend in precipitation [16–18] and the changes in water use efficiency [11] at the same time without knowing which mechanism is relatively stronger. Finally, we discussed the validity of the findings through the analysis of historical observations.

#### **2. Materials and Methods**


*Edited by Khalid S. Essa*

This book presents a comprehensive overview of gravity and gravitational fields. The eight chapters are presented in two sections. Chapters in the first section address such topics as the theory of gravity, transient gravitational forces, the nature of our temporal universe, and photo-gravitational celestial mechanics. Chapters in the second section discuss how to create a gravity survey, analyze data collected by satellites and on the ground, and present visualizations of several field cases around the world.

Published in London, UK © 2022 IntechOpen © IncrediVFX / iStock

Gravitational Field - Concepts and Applications

Gravitational Field

Concepts and Applications

*Edited by Khalid S. Essa*


**2.30 Trypsin inhibitor**

224 Gamma Radiation

These mutants showed superior yield attributes such as length and number of pods, number of seeds, 1000 seed weight and yield per plant as compared to control (Plate- 4). Auti (2005) stated that some unknown mechanism must be inducing the expression of yield controlling genes, which are responsible to increase the yield. Same may be the reason for getting high yielding mutants in horsegram. These mutants can break the constrains of low yield of

The seeds of all viable mutants showed reduced which will be of immense importance for the feature development of desirable varieties of horsegram with improved nutritional

The results shown in Table- 6 revealed that all the mutants except dwarf and compact showed decrease in phytate content. Phytic acid decides the nutritional quality of cereals and seeds of legume as it is a strong antinutritional factor. It is also implicated in the "hardto-cook" phenomenon of legumes (Stanley, 1985). Hence development of new cultivars with low phytate is the prime need of time. In present study tall, high yielding, early, late and long pod mutants showed reduced phytic acid contents (Table- 6). All such mutants can be exploited in future hybridization programme of horsegram aimed for improving nutrient

Control 442.25±17.69 2639.71±105.59 185.81±7.43 Tall 420.12±21.01 2565.51±128.28 110.43±5.52 Dwarf 447.14±31.30 2647.94±185.36 104.19±7.29 Compact 408.55±12.26 2643.83±79.31 120.71±3.62 Early 396.26±23.78 2425.56±145.53 98.75±5.93 Late 412.21±16.49 2544.99±101.80 126.96± Long pod 411.37±28.80 2372.45±166.07 136.32±9.54 Broad pod 409.07±12.27 2641.59±79.25 129.98±3.90 High yielding 402.26±24.14 2289.66±137.38 138.65±8.32 SEM± 17.81 106.29 5.36 F-Value 1.88 3.24 46.18 P-Value 0.13 0.02 0.00 LSD0.05 37.42 223.32 11.26

Data are means of three replicates ± standard deviation. Significant difference due to treatments was

Table 6. Nutrient quality in seeds of M3 mutants of horsegram cv. Dapoli Kulthi 1

**Phytate**  (mg 100g-1) **Trypsin inhibitors**  (TIU)

**2.27 High yielding**

horsegram, in rainfed agriculture.

**Mutants Polyphenols**

assessed by Fisher's LSD as a post-hoc test.

(mg 100g-1)

**2.28 Antinutrients in seeds**

**2.28.1 Polyphenols**

quality.

quality.

**2.29 Phytate**

All the mutants showed decreased levels of trypsin inhibitor over control. Lowest values of TI were found in early mutant (98.75 TIU). The values of TI in different mutants in order as given below dwarf > tall >compact >late >long pod >high yielding.

The legume seeds like horsegram contain trypsin and chemotrypsin, which are the main anti-nutritional factors (Chavan and Hejgaard, 1981) as they decreases the digestibility of protein and cause pancreatic hypertrophy (Manjaya *et al*., 2007). The decrease in the levels of trypsin inhibitor as a result of the treatments of mutagens was reported by Harsulkar (1994). Kim *et al*., (2010) reported increase as well as decrease in trypsin inhibitor in mutants induced by gamma radiation. The mutants of horsegram with low TI have a great role in vegetarian diet of Indians.


**Cervical Disc Arthroplasty**

Bruce V. Darden

 *OrthoCarolina Spine Center, Charlotte USA*

### **1. Introduction**

For more than 50 years, anterior cervical discectomy and fusion (ACDF) has been the workhorse procedure for cervical degenerative pathology. (Bailey & Badgely, 1960; Cloward, 1961; Robinson & Smith, 1955) The procedure has yielded successful results clinically in multiple large series. (Bohlman et al, 1993; Gore & Sepic, 1984) Advances in allograft and cage techniques as well as the use of anterior plating systems have diminished complications in ACDF. However, concerns about adjacent segment degeneration (ASD) have tempered some enthusiasm for the procedure. Gore et al (Gore & Sepic, 1998) reviewed a series of 50 ACDF patients followed long term. Almost universally, the patients developed ASD. One-third of the cohort developed recurrent pain with half of the symptomatic group requiring additional surgery. Hilibrand et al (Hilibrand et al, 1999) evaluated a group of 374 patients undergoing ACDF. They showed a 2.9% per year risk of development of symptomatic ASD, with two thirds of the symptomatic patients requiring additional surgery. Goffin et al (Goffin et al, 1995) prospectively followed a series of ACDF patients who underwent the procedure for either a degenerative or traumatic condition. Follow-up was for five to nine years. Sixty percent of the patients developed ASD, equally distributed between the older degenerative population and the younger traumatic population, providing evidence that fusion may accelerate degenerative changes. Goffin et al (Goffin et al, 2004) reviewed a larger series of ACDF patients followed for an average of 8.3 years. In this group, 92% of the patients developed ASD, though they had a much lower rate of additional surgical procedures, 6.1% for the entire length of follow-up, distinctly lower than Hilibrand et al. Numerous cadaveric biomechanical studies (Eck et al, 2002; Pospiech et al, 1999) evaluating adjacent level intradiscal pressures and range of motion in simulated fusion models have shown that both increase after fusion. These altered biomechanics may thus accelerate ASD.

Against this background, centers began experimenting with cervical disc arthroplasty in the 1980s. Cummins and collaborators at the Frenchay Hospital, Bristol, England developed a metal-on-metal ball and socket arthroplasty and implanted it on a small series of patients in the 1990s. (Cummins et al, 1998) The arthroplasty underwent a number of design changes and is now known as Prestige. Bryan, in the US, developed a one piece metal-on-polymer device called the Bryan Cervical Disc Replacement, initially evaluated clinically in Europe. (Goffin et al, 2002) ProDisc-C arthroplasty is a metal-on-polyethylene implant adopted from the ProDisc-L lumbar disc arthroplasty developed by Thierry Marnay. (Delamarter & Pradhan, 2004) Since

Cervical Disc Arthroplasty 501

Bryan Cervical Disc Prosthesis (Medtronic Sofamor Danek, Memphis, Tennessee) consists of a nucleus made of polyurethane between two titanium alloy endplates in a clamshell configuration. (Figure 2) There are two bearing surfaces in the arthroplasty at the interfaces between the nucleus and the endplates. A polyurethane sheath attaches to the endplates and surrounds the nucleus. Sterile saline is injected between the outer sheath and the nucleus as lubricant. The endplates have a titanium porous coating for bone ingrowth and a small

ProDisc-C Cervical Disc Prosthesis (Synthes, West Chester, Pennsylvania) has a ball and socket design, with endplates made of a cobalt-chrome alloy. The endplates have keels for immediate fixation and titanium plasma spray backing for bone ingrowth. The bearing surface has an articulating dome of ultra high molecular weight polyethylene (UHMWPE) attached to the inferior endplate and a concave polished socket integral to the superior

**2.2 Bryan Cervical Disc Prosthesis**

flange anteriorly to prevent posterior migration.

(Courtesy of Medtronic Sofamor Danek, Memphis, Tennessee)

Fig. 2. Bryan Cervical Disc Prosthesis

(Courtesy of Synthes, West Chester, Pennsylvania)

Fig. 3. ProDisc-C Cervical Disc

**2.3 ProDisc-C**

endplate. (Figure 3)

these first three devices have been developed, the number of cervical disc arthroplasties has proliferated. The literature in this nascent field is limited, but growing each year.