Otra vez la burra al trigo ...

Ninguna economía se puede sostener mediante muletas contributivas y mantengo corporativo. Ninguna.

El propuesto cambio a la sección 933 es para que se use la banca de PR como conducto para que empresas multinacionales puedan repatriar hacia USA sus ganancias obtenidas en el exterior. El que se crea que ésto va a traer plantas manufactureras u algún otro tipo de empleo a PR se llevará tremenda decepción.

Quienes realmente se benefician de ésta propuesta enmienda 933A son la banca local (que históricamente ha contribuído millones al Partido Popular y a mantener la colonia), los accionistas de los bancos locales (como los Ferré Rangel, Sila María Calderón, etc) y los grandes bufetes como McConnell-Valdés (¡que coincidencia, el bufete de donde salió Fortuño!) que perdieron muchísimo dinero cuando las ex-936 dejaron de usar sus servicios, y por supuesto el Partido Popular, que nuevamente recibirá ayuda multimillonaria de éstas empresas cada vez que haya que torpedear, obstaculizar y hundir procesos descolonizadores.

El neoPNP con ésta movida acaba de convertirse oficialmente en el hederedo del PPD como el partido de los Happy Colonials ligeramente pro-americanos.

Para que una economía prospere tiene que levantarse sobre sus propias ventajas comparativas, sobre características y fortalezas propias, inherentes, no sobre inventos y traquetelos leguleyos que pueden desaparecer con un plumazo del Congreso.

PR tiene que levantar sus propias empresas, echar a andar sus propios start-ups, tener disponible capital de riesgo para inversiones, invertir en incubadoras de tecnología, para que surjan empresas locales que puedan ser el fundamento de una economía propia que invierta aquí, no una economía prestada que viene y se va según sople el viento económico mundial.

Y para atraer inversiones Puerto Rico tiene que corregir sus eternos problemas, que joroban tanto al inversionista como al empresario local como a los residentes: el alto costo y pésimo servicio de electricidad y agua, el pésimo estado de la infraestructura, la espantosa criminalidad, el alto costo de la transportación, las leyes laborales prehistóricas y retrógradas, y la tramitología elefantiásica del gobierno estatal.

Arreglen todo eso y se reducen los costos de operar en Puerto Rico no sólo para las multinacionales sino para los empresarios locales, que viven asfixiados por el peso de todas esas cosas. Arreglen eso, inviertan en startups de tecnología tendrán un fundamento fuerte para la economía de la Isla que NO DEPENDERÁ del status político, ni de muletas contributivas, ni de mantengo corporativo.

Yo dudo que el Congreso, que está como loco buscando fuentes de ingresos en medio de un déficit cuasi-apocalíptico, vaya a aprobar un tax loophole tan enorme como éste. Probablemente aprobarán un tax holiday de 12 meses directo con el IRS, sin usar a PR como conducto. Pero de aprobarse éste embeleco, olvídense que lo que hay en PR es 100 años más de coloniaje.

El que ACEPTE que lo traten como a un SÚBDITO COLONIAL en vez de como a un CIUDADANO, pues se merece los maltratos y las injusticias que le caigan encima.

- Yo
hoy.

Particles Found to Travel Faster than Speed of Light

ésta noticia recorrió el mundo hoy ...

http://www.scientificamerican.com/article.cfm?id=particles-found-to-travel

This result is not yet conclusive. When something like this happens, a LOT of research, confirmation, requete-confirmation, attempts to duplicate results, etc. must be performed BEFORE they can conclude that those neutrinos were indeed moving at speeds higher than light.

If this observation turns out to be a true discovery, it may require a revision of relativity as it is known today. But most likely it will not overturn it completely. :-)

I am VERY rusty in my fundamental physics, so please forgive me if this opinion turns out to be nonsense X D

PS : if you are interested on reading the original paper where this came out, it's available HERE:

http://arxiv.org/ftp/arxiv/papers/1109/1109.4897.pdf

Aprendiendo de Otros

Los puertorriqueños tienen que aprender de las luchas de otros.

Décadas atrás, cuando en los estados del Sur se les negaba irresponsablemente a los ciudadanos negros la igualdad de derechos, éstos no se dieron por vencidos. Ellos insistieron en su lucha pacífica, y lograron deslegitimizar el sistema segregacionista al punto de que se hizo social y políticamente insostenible para el gobierno mantenerlo. Gracias a su lucha consistente y firme, la segregación colapsó, y los negros lograron obtener la igualdad de derechos que la Constitución les garantiza.

El Estado Libre Asociado, ese embeleco injusto y criminal que mantiene a Puerto Rico sumido en el subdesarrollo y el tercermundismo colonial, no es otra cosa sino una forma moderna de Apartheid, de segregación étnica, que sobrevive mediante subterfugios y pretextos, para proteger los intereses económicos de unos pocos a expensas de los derechos y la prosperidad de la inmensa mayoría.

Es necesario deslegimizar el coloniaje en las esferas de poder politico, y en los medios de telecomunicación masiva de los 50 estados. Hay que insistir, fastidiar, jeringar, hasta que la existencia de ese sistema segregacionista, discriminador y criminal llamado “ELA” se convierta en un liability. Hay que deslegitimizar completamente el coloniaje, delatarlo como el grotesco engendro racista que es, hasta el punto en que nadie en el Congreso, ni en el poder Ejecutivo , ni en las multinacionales se atreva a apoyarlo nunca más.

Para eso es que se supone que en Puerto Rico existe un partido “estadista”. El PNP no debe esperar a que el status de Puerto Rico se convierta en un asunto de importancia para el Congreso; la responsabilidad de un partido estadista es HACER que el status de Puerto Rico se convierta en un asunto de importancia. La organización y ejecución de éste tipo de campaña de medios masiva para retratar al ELA como lo que realmente es debería ser trabajo de Luis Fortuño, Pedro Pierluisi, Kenneth McClintock, Thomas Rivera Schatz, Jennifer González, y el resto del liderato del PNP. El PNP debería pedir tiempo en cuanto programa de discusión política existe en las cadenas nacionales de television, marroneando el punto ad nauseaum ante cada pundit de la derecha y la izquierda.

Ganar un plebiscito no es la meta, es apenas el principio. Tal vez no se obtenga la estadidad aunque ésta gane un plebiscito de status con 49%, o aún con 52%. Pero una victoria plebiscitaria, con los números que sean, levantará el issue de una forma significativa en los medios nacionales. Entonces le tocará a todos esos que mencioné antes irse a chavar , jeringar y mantener el issue vivo hasta que se logre una resolución final.

Es por eso que había que realizar el plebiscito en 2009, y no esperar a tener 3 años de issues y peleas entremezclados con el issue del status.

Pero más vale tarde que nunca. El pueblo estadista debe presionar a su partido estadista para que realizen el plebiscito y para que NO DEJEN MORIR EL ISSUE después del resultado.

The Myth of Pedro Albizu Campos

The Myth of Pedro Albizu Campos

by Raul Soto

November 9, 2000

[NOTE: Since a number of people have in the past expressed interest in using some posts for radio programs or other types of communications in the States, I'm sending this in English to save you all the trouble of translating it. ]

One of the most interesting things about today's 'independentismo' is its nationalistic streak, and their newly-found devotion to the figure of Pedro Albizu Campos. T-Shirts, posters, portraits, and quotes of Albizu are common in 'independentista' nazionalist rallies around the Island and in the US.

But how just much of what they say about Albizu is true, and how much is product of historical revisionism, of an attempt to manufacture a legend, a mythical hero, marthyr, prophet and leader, which can be used to rally together and unite the numerous pro-independence tribelets?

Here are some of the most common myths about Pedro Albizu Campos and some answers to them, from a conversation a statehooder friend of mine had with an Independentista professor from the UPR :

1. Albizu dedicated his life to be the lawyer of the workers and the poor

This is a lie. After 1937, Albizu spent most of his time perpetually in jail, not because he "dedicated his life to the poor", but because he was perpetually inciting those of weaker minds to violence.

2. Albizu was the President and Leader of one of the most influential political parties of his era

The Nationalist Party, contrary to this claim, was numerically tiny (just look at the 1932 election results, less than 4,000 votes). Of course, old Pete couldn't deal with the fact that *practically nobody* liked him. This, by the way, included INDEPENDENTISTAS themselves (think his color had to do something with that? Doesn't anybody find curious that all those lilly-white present-day "patriotas" who wouldn't be caught DEAD shaking the hand of a black man, give all these hellium-filled speeches about Albizu? I'll tell you why - because he's DEAD. If he were alive, Mari, Gallisá, Fufi Santori, Muriente, Farinacci, and yes, the little troika of Ruben, Fernando and Manuel wouldn't touch him with a ten foot pole). So dear old Pedro, after his crushing electoral defeat, decided to denounce the electoral process (talk about a sore loser).

I guess it all comes down to how one defines "influential". If by influental one means a small rabble of black-shirted (just like Mussolini's boys. Coincidence? Read on...) fanatics running amok and attempting to (and succeeding, as in the case of Riggs) murder anyone who disagrees with them (they even tried to off Santiago Iglesias, the labor leader, because he was pro-american), then I guess they might be 'influential'.

3. With his potential, his education, experience and proven intelligence, he could have been rich, successful, and maybe even challenge Luis Muñoz Marín for political power in the colony.

There's an old Aerosmith tune called "Dream On", and the title applies here. Albizu wouldn't have been elected dog catcher. Just ask any old geezer who lived through that era. Albizu was the kind of guy whose speeches are perhaps fun to listen (if you like screaming), but who scares the bejeezus out of people if the prospect of his gaining power became a reality.

Besides, he went to the polls only ONCE, and he got LESS than 4,000 votes. Some potential for political power...

4. Albizu decided to give his life, talents in the struggle for the freedom of Puerto Rico, when PR was threatened with the loss of its culture and "collective being" under the forced-americanization programs of the 20's and 30's

And instead, he was a sickening Hispanophile (funny, he wasn't into mentioning his African side) who even supported Franco, and before that, the Spanish Monarchy. Of course, all good fascists stick together.

Think about that, the grandson of people who were brought to the Island as SLAVES, under the lash and the most cruel conditions, and he supports the very regime that enslaved his family. Well, if statehooders are "pitiyankis", does that mean that Albizu was a "piticatalán" o "pitigallego"?

As for this "collective being" psychobabble: get real, we're all INDIVIDUALS. By the way, what happened to the Spaniards who populated the Island and then became Puerto Ricans, who took away their "collective being"? And why is it OK for that to have happened, but ANY kind of cultural influence from the US is not? And what about the Africans? You're not going to tell me that those folks were Catholic, ate rice and beans, and spoke Spanish in Ghana and Guinea, now are you? What happened to their "collective being"?

5. One can disagree with his rethoric and his methods, as the PIP did, and perhaps his personality, but no one can dismiss that he's a central figure in our history, because he directed a movement of people with the balls to risk their lives, families and property to fight for the freedom they thought was necessary

Hogwash. Albizu is a pimple in the history of Puerto Rico. He had NO popular support, his political thinking was profoundly FASCIST; he was also a conservative catholic who probably would have persecuted protestants, and he was NO FRIEND of labor, as you and the PIP would have us believe.

Remember what Albizu's solution to the cane workers' was during the strike of 1934-35? "Les daremos hombres de talla". As The Who put it: "Here's the new boss. Same as the old boss".

The quicker Albizu and his message of HATRED and DIVISION is relegated to the dustbin of history, the better off the Island will be. And, let's not forget, at his most violent, the PIP was the #2 party in Puerto Rico, poised to challenge the PPD for control of the Island. And just then Albizu and his yahoos decided to go for a coup d'etat. Ironic, ain't it? That the guy who spewed forth so much blather about independence is probably the guy responsible for hundreds of thousands of PRs turning AWAY from independence, and towards the USA? That's right, Albizu scared the hell out of people of that time. Incidentally, the Jayuya and Utuado fiasco is also where the independentistas got their "foaming at the mouth, bomb throwing, wild-eyed, raging lunatics" stereotype. If he had only let Concepción de Gracia and his guys do their stuff...

But no, as with all megalomaniacs, "I did it MY way"

6. We have to admire him for the same reasons that the world admires Washington, Bolívar, Sandino, Zapata, Mandela, Martin Luther Kind, José Martí, Maceo, San Martín and many others; because he decided to fight a clearly superior enemy, because he loved his people and wanted their freedom.

BS. It shows a remarkable lack of historical knowledge, or a serious ideological blindness, to say that. Unlike the men mentioned above, ALL of whom had MUCH MORE popular support than Albizu ever did, Albizu led a FASCIST movement (did you know what's the German word for Nationalist? NAZI). And you know what Fascism is all about, right? Well, we saw what it did in Europe during the 20's, 30's and 40's, right? And in Spain until the 70's. In fact, look at Milosevic, a good old nationalist if there ever was one. And this is to be admired???

And again, in 1948 the PIP got more than 22% of the vote. Why couldn't Albizu cooperate with them, his fellow independentistas? I'll tell you why, because his EGO got in the way. Funny, even TODAY, independentistas have more ego than camaraderie among themselves. Some things (and some people) never change.

Oh, and another thing: Fidel was in the Sierra Maestra with his troops. Washington was with his, crossing the Delaware. Bolivar put his own lands and his own money on the line to be with his troops. So did Mao during the "Long March". But WHERE was Albizu while his "troops" tried to take over Barrio Obrero, Jayuya and Utuado? Was he on the front, giving orders? Was he on a hand-to-hand battle against the oppressor or his colonial lackeys? NO! He was HIDING in an apartment in Old San Juan, and he came out naked, wrapped in a white towel, when the Police got him.

What a leader (not) !!!

7. He's worthy of an important place in the history of Puerto Rico and the Americas

I betcha if he were alive, YOU would be the first one to want him committed...

8. Statehooders say that Albizu was a terrorist. That's what the British said about Washington and his rebels, the Salvadorian oligarchy about the FMLN, Pinochet about Allende's people, Somoza and Batista about the guerrillas that confronted them, and so on. Each person should decide what his/her position in the political spectrum should be

The truth is that ALL those guys mentioned there had some measure of popular support, but Albizu? ONLY AFTER HE WAS SAFELY IN THE GRAVE. And even then it would be less than 3%.

Albizu is a freaking myth created by the pseudo-intellectual petit-burgeois of the ivory towers, so that they could have some hero to follow and to brainwash impressionable minds with some of that good ol' patriotic fervor.

But not to worry, PRs have more common sense than that.

9. If Albizu was so insignificant as statehooders desperately claim, then why even mention him? One doesn't waste a pixel to criticize a myth, unless of course one views him as a threat

Just because someone disparages Albizu doesn't mean that he's a threat. Besides, the guy's been safely dead for over 30 years; and, at last glance, other than the usual blather from the ivory tower independentista set, his movement (mind you, I'll be GENEROUS and include ALL the independentistas under the same tent, although how the Frente Socialista with its classic adherence to Marxist crud, and the Partido Nacionalista with its adherence to Fascist standards get together is beyond me) has NO POPULAR SUPPORT. So, some threat.

10. Every movement has its heroes, and one of the PR Independence Movement's heroes is Albizu, for his dedication and courage to put his life in the line for his beliefs and the independence of Puerto Rico

Did you know that one of the requirements to practice Law in Puerto Rico is to swear loyalty to the US Constitution? So there's your 'patriot', swearing loyalty to the supreme law of the supposed oppressor. Albizu did it; as casey Stengel said "You can look it up".

11. Say what you want, and spin your disdain for Albizu any way you like. The fact remains that Albizu, as a man, may have been as flawed as any man is. But as a symbol of independence, of sacrifice, of love of his country, he will never lose his place in our history and in our hearts,

I assume that you speak for yourself. To me, he is the symbol of fanaticism, of racist hatred, and of immature passion. A guy who could have contributed a lot, but instead he wasted his life away.

12. The myth has public streets named in his honor, books written about his life and struggles, monuments stand for his memory. These things stand in diametrical contradiction to your ravings, and place him in the realm of the Titans of our independence movement as José de Diego, Betances, etc.

So? That's precisely the point. He's a myth created by the pseudo-intellectual petit burgeois of the ivory towers; and the monuments, books, and everything else is done in order to manufacture a Puerto Rican Bolívar, or Washington.

De Diego? Wasn't he Central Aguirre's lawyer during the sugarcane worker's strike? See, that's the essential problem with the supposed "independentistas" (really, now, isn't the sad truth that most of you talk the talk, but when it's time to walk the walk you get the shivers and vote Popular?). On the one hand, a lot of this "patriotero" talk; but on the other hand, it's TOTAL adherence to the status quo. What did Jacobo Morales call it? Oh, yeah, "Patriotas de Cafetín"...

13. You are sadly mistaken when you state "Albizu is a fricking myth created by the pseudo-intellectual petit burgeois of the ivory towers"

Where's the proof behind your claim? The FACT is that Albizu only went to the polls ONCE, and got LESS THAN 4,000 VOTES. Is that what you call a leader? When he was in jail, the VAST MAJORITY of Puerto Ricans, including Independentistas, were totally in agreement. It is only NOW, that he is safely dead and harmless, that he is supposedly venerated. Why?

14. More accurately, he was a product of the military colonial establishment of the US and their policies to erase our existence as a distinct culture

Really? The first thing is that by 1901, there was a CIVILIAN government in PR. The very first in our history, since Albizu's beloved Spaniards had never seen it fit to permit PRs to be ruled by civilians. There was also a Legislature that enacted all of the local laws, another first for PR.

As far as "erasing our existence as a distinct culture", the fact is that just as the Spanish imposed their Castilian language on the Taínos and the Africans they brought here under the lash, the US attempted to teach English (let's not even get into the historical fact that the FIRST public school system in PR was also part of the benefits of US rule, the Spanish believed in keeping the majority of the population illiterate and ignorant). Funny, all the hullaballo about English in the schools and not a single peep about the cultural GENOCIDE the Spanish perpetrated against the Africans and Taínos.

Albizu was more of a product of an illegitimate birth by a white man (a Spaniard) who did NOT recognize him as his son until Albizu was an adult, and of the racism of his independentista peers. Of course, to admit that his OWN kind rejected him because he was black would be too big an admission, right? Better to reject "the invader" than to actually look at Puerto Rico's society for what it REALLY was, and to a large degree, continues to be.

15. Albizu was the manifestation of the Puerto Rican Nation immune system, in raising to the defense of its identity. Without colonial rule, there would have been no Albizu, no need of him

The problem with what you say is that you seem to believe that there is some kind of "collective thought process" going on. Perhaps the Borg are like that, but human beings, and certainly Puerto Ricans, are not. The fact is, of course, that we are ALL individuals, unique, each and every single one of us. I don't want to burst your bubble, but I betcha if you ask 100 people what a Puerto Rican is, or what is the "Puerto Rican nation", you're going to get 100 totally different answers.

Albizu was simply a man faced with tremendous racism, rejection by both the blanquito society in PR and the racist society up north (although, with all the racism, he DID manage to go to Darmouth and Harvard. That's one hell of a way to stamp someone out, isn't it? By letting them go to the most prestigious institutions you have? To this day, independentistas are the maximum beneficiaries of the system they so delight in condemning. I wonder what would happen if it really came down to crunch time?)

Faced with that, he goes into this fantasy world where under the Spanish (notice that his father was a Spaniard that never took care of him. One could easily conclude that Albizu's EXTREME Hispanophilia was simply the little boy in search for the father that never was) everything was all right and all Puerto Ricans were taken care of. A culturally homogeneous Puerto Rico, where everyone had the same values and so forth.

What folly! It was false then and it is false now. Which, I guess, is probably one of the prime reasons Albizu couldn't get much popular support then...

Triangulando

TRIANGULANDO

http://www.elnuevodia.com/legislanobligatoriedaddereflectoresenlosvehiculosdemotor-1059855.html

Ésto es lo que hacen los LegisLadrones para tapar que no tienen ni perra idea de cómo mejorar las cosas en la Isla : añadir MÁS formas en que te puedan clavar con un boleto y tumbarte tu dinero.

El que te va a llevar enredao, te lleva enredao con o sin triangulito.

Eso sí, como bien dijo alguien ya, el importador de esos triangulitos va a vender de repente más de 1 MILLÓN de unidades, y se va a JARTAR de $$$.

¿Saben lo que SÍ DEBERÍA ser ley, pero no lo es en PR? Que exista un website como OpenSecrets.com donde el pueblo pueda ver QUIEN le dona dinero a cuál político, CUÁNTO y cuándo.

Así, por ejemplo, podríamos ver a cuáles políticos les dará $$$ el importador de los triangulitos :-)

Apartheid en el Caribe

Apartheid en el Caribe

Ahora que el Gobernador Luis Fortuño ha anunciado la celebración de un plebiscito de status, es imperante educar a los puertorriqueños, particularmente a los estadistas, sobre lo que realmente es el ELA.

En las escuelas públicas nos metieron a todos en la cabeza los cuentos aquellos de que el ELA era un “status de avanzada”, “lo mejor de los dos mundos”, mezcla de Utopía y Disneylandia, la razón por la que no andamos en taparrabos comiendo piedras. Todavía hoy demasiada gente sigue creyéndoselo, aunque baste salir a la calle para ver que es mentira.

Pero si rebuscamos debajo de la retórica embrutecedora del Partido Popular, nos damos cuenta de que el principio fundamental tras el ELA es que como los puertorriqueños son “diferentes”, no pueden tener los mismos derechos y privilegios que los demás ciudadanos americanos. ¿Y de dónde salió una idea tan retrógrada? De la segregación.

La gente que se inventó el ELA durante la primera mitad del siglo 20 fueron los mismos racistas que validaron y enforzaron las leyes Jim Crow en el sur de EEUU, imponiéndole a los negros un status legal inferior, discriminatorio y racista – porque eran “diferentes”. El ELA salió de esa misma mentalidad - es un engendro racista, retrógrado, un tipo de apartheid y de segregación creado hace más de medio siglo para oficializar el discrimen contra los puertorriqueños. Por eso nuestros estudiantes, nuestros enfermos y nuestros ancianos reciben mucho menos dinero federal. El ELA significa MENOS becas, MENOS Seguro Social, MENOS Medicare. MENOS justicia.

Los EEUU comenzaron a dejar atrás esa etapa con el movimiento de derechos civiles en los 1960s, que culminó con la derogación de la segregación. Con la elección de un presidente de ascendencia africana, los EEUU han demostrado que la mayoría de la nación se zapateó de encima el demonio del racismo.

EXCEPTO en Puerto Rico.

Los negros lograron deslegitimizar la segregación. Hoy se considera algo tan inhumano y asqueante que apoyarla es políticamente insostenible, suicidio para cualquier politico. ¿Acaso el coloniaje que mantiene cuatro millones de puertorriqueños en un status de perpetua inferioridad política es menos inhumano y asqueante?

Ya es tiempo que el Comisionado Residente proclame a viva voz en el Congreso que el ELA es una verguenza inaceptable, una mancha racista sin lugar en una nación libre, democrática y progresista. Ya es tiempo de que el mundo vea al ELA como lo que es: una reliquia racista, un tipo de apartheid espantoso diseñado para segregar a los puertorriqueños en una reservación caribeña, con menos derechos y menos privilegios que los demás. El ELA colonial es una alternativa tan impensable en un plebiscito como la segregación.

Una vez se logre deslegitimizar al ELA, una vez lo desenmascaremos como el engendro racista que es, una vez congresistas a sueldo como Nydia Velazquez y Luis Gutiérrez dejen de a apoyarlo a cambio de dinero del PPD, ENTONCES Puerto Rico podrá finalmente decidir su futuro entre opciones reales: la estadidad, la independencia, y la libre asociación.

Rheumatoid Arthritis: Overview, Molecular Mechanisms and Biologics Treatments

Rheumatoid Arthritis: Overview, Molecular Mechanisms and Biologics Treatments

Raul Soto-Velez^1, BSME

¹ MS Biotechnology and Bioinformatics program, California State University Channel Islands, Camarillo, California

Abstract

This paper presents an overview of rheumatoid arthritis, its demographics, and descriptions of the main molecular mechanism of disease and biochemical pathway. The main available treatments are discussed, with emphasis on biologicals. Finally, a new drug is proposed, and its mechanism of action, effect in the disease’s main molecular pathway, proposed delivery methods, formulation options, and cost estimates are described and discussed.

Keywords: rheumatoid arthritis · TNFα · interleukin · cytokines

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic, progressive autoimmune disease [Choy, 2001][Dudler, 2011][Shin 2009][Hekmat, 2011], characterized by the symmetrical inflammation of the synovial lining of the small joints of the hands, wrists, feet, and knees [Rasch, et at. 2003] [Shiel, 2011]. It is the most common type of inflammatory arthritis [Firestein, 2003]. The disease ultimately leads to the destruction of the cartilage, erosion of the bone, and deformities in joints [Moreland 1999][Shin 2009]. At its most advanced stage, rheumatoid arthritis leads to loss of functionality of the joints [Dudler, 2011].

Various cell types are involved in the initiation and progression of rheumatoid arthritis, among them B cells [Bokarewa, 2007], T cells [Firestein, 2003], macrophages [Boilard 2010], mast cells [Shin, 2009], and platelets [Boilard 2011]. Various signaling molecules are also involved in the mechanisms of disease, including inflammatory and destructive mediators such as cytokines, prostaglandines, and metalloproteinases [Bresnihan, 1998].

Two cytokines in particular, tumor necrosis factor alpha (TNFα) and interleukin – 1 beta (IL-1β) have been found to be the main players in the biochemical pathways that cause inflammation and cell death in rheumatoid arthritis [Bresnihan, 1998]. Other cytokines involved in rheumatoid arthritis are interleukin-6, interleukin-10, interleukin-4 [Choy, 2001], and interleukin-17 [Chabaud, 1998][Kotake, 1999]. Other cytokines such as interleukin-23/17A are expressed in limited amounts in patients with advanced rheumatoid arthritis, but do not have a large role in the disease [Hillyer, 2009].

Demographics and Social Impact

Rheumatoid arthritis is the most common of all inflammatory arthritides [Lawrence, 2008]. It occurs in approximately 0.5 % – 1.0 % of the world’s population [Lundkvist, 2008], and in approximately 2% of people aged 60 or above [Rasch, 2003] in the United States.

Prevalence of rheumatoid arthritis appears to increase with age [Lundkvist, 2008]; in the United States, for people aged between sixty and sixty nine years, prevalence has been estimated to be between 1.59% - 1.89%; while for people aged sixty years or older, it has been estimated to be between 2.46% - 2.80% [Rasch, 2003].

Rheumatoid arthritis has significant social and personal costs [Choy, 2001]. Patient’s life expectancy is reduced by between three and eighteen years [Choy, 2001]. Presently there is no cure for rheumatoid arthritis [Choy, 2001] [Dudler 2011]. Within twenty years, 80% of rheumatoid arthritis patients are disabled and unable to work [Choy, 2001].

Genetic factors appear to have an important role in the susceptibility to rheumatoid arthritis, and a number of genes have been identified as related to the pathogenesis of the disease and as potential targets for treatments [Perricone, 2011]. In the United States, Mexican-Americans have a higher rate of rheumatoid arthritis that non-Hispanic whites, while African Americans have a lower rate [Rasch, 2003]. The prevalence of rheumatoid arthritis in women is approximately 150% higher than in men [Rasch, 2003].

The social and economic costs of rheumatoid arthritis have been estimated to be approximately 41.6 billion euros (US $59.94 billion) in the United States, and 45.30 billion euros (US $65.27 billion) in Europe [Lundkvist, 2008].

Diagnosis

A new classification criteria, which provides specific guidelines for the diagnosis of rheumatoid arthritis, was published in August 2010 [Kaneko, 2011].

A combination of various diagnostic methods is used to diagnose rheumatoid arthritis [Shiel, 2011]. Blood tests are typically done to perform immunological assays that detect the presence of antibodies associated with rheumatoid arthritis; such as rheumatoid factor (RF), antibodies to cyclic citrullinated peptides (anti-CCP) [Schellekens, et al, 2000], and antinuclear antibody (ANA) [Shiel, 2011]. Other blood tests commonly used in the diagnosis of rheumatoid arthritis are the elevated erythrocyte sedimentation rate (ESR) test; and testing for the presence of C-reactive protein, which correlates to inflammation in the body [Shiel, 2011].

Radiography (X-rays) is commonly used to follow the progress of the disease by monitoring the erosion of the joint bones and the inflammation of soft tissue in the joints [Shiel, 2011].

Magnetic resonance imaging (MRI) has also been investigated as a diagnostic tool for early detection rheumatoid arthritis [Suter, 2010]. Magnetic resonance imaging is able to detect erosion in the joint bones and inflammation in the synovium at an earlier stage than X-Rays [Suter, 2010].

Mechanism of Disease

Figure 1 shows a comparison of a healthy joint against a joint afflicted with rheumatoid arthritis.

The inflammatory process is normally regulated by mediators that initiate the inflammatory response and mediators that inhibit it [Choy 2001]. In rheumatoid arthritis patients these regulators are not balanced, which allows an increase in inflammation that leads to tissue damage and destruction [Choy 2001].

In a normal, healthy joint, a layer of cartilage tissue covers and protects the ends of the bones, surrounded by a synovial membrane which consists of a layer one or two cells thick [Choy, 2001] and which holds the synovial fluid that lubricates and nurtures cartilage tissue [Lee, 2007].

In a joint with early rheumatoid arthritis, the synovial membrane becomes inflammated and thickens due to hyperplasia and hypertrophy of the cells that line the synovium, and begins to invade the cartilage tissue [Choy, 2001]. The synovial membrane is infiltrated by T cells and B cells [Choy, 2001].

When rheumatoid arthritis reaches a more advanced (established) state, the inflammated synovial tissue becomes the pannus, inflammatory tissue that invades and destroys the bone and cartilage in the joint [Choy, 2001].

Figure 1: Pathogenesis of Rheumatoid Arthritis (Choy 2001)

It is not yet known what triggers the immune response that causes the body’s antibodies to attack the cartilage and the synovial membrane [Shiel, 2011]. It is known, however, that increased expression of inflammatory cytokines such as TNF α, IL-1, IL-6, and others has a key role in the inflammatory response and tissue destruction elements of the disease [Egan, 2003].

The mechanisms that control the secretion of cytokines are not completely known [Chaofeng, 2009]. Lymphocytes are attracted to the site where antibodies attack the joint tissues, where they differentiate into macrophages and release cytokines such as tumor necrosis factor α (TNF α), interleukin-1 (IL-1), and interleukin-6 (IL-6) [Shiel, 2011].

TNFα increases the expression of adhesion molecules in endothelial cells, which in turn recruits additional immune cells to the site of the attack, amplifying the immune response [Choy, 2001] [Shiel, 2011]. IL-1 and IL-6 act as signaling molecules, also recruiting more immune cells to the afflicted area [Choy, 2001]. IL-1 is an important mediator of the autoimmune response, bone resorption and cartilage damage in rheumatoid arthritis, although it is not a major mediator in inflammation or joint swelling [Schiff, 2000]. Exposure to IL-1 and TNFα stimulates the expression of IL-6, another inflammatory cytokine [Ishimi, 1990] [Palmqvist, 2002] [Palmqvist, 2008]. TNFα and IL-1β regulate gene expression in microphages and in fibroblast-like synoviocytes, stimulating the expression of cytokines such as IL-6, IL-8, while reducing the expression of IL-17 [Mi Choi, 2010]. The combined effect of all these factors increases the joint damage caused by the degradation of connective tissue [Choy, 2001].

Elevated levels of TNF α and IL-1β have also been found to induce osteoporosis in rheumatoid arthritis patients by up-regulating the apoptosis of osteoblasts [Tsuboi, 1999]. Elevated levels of cytokines such as TNF α and IL-1β have also been linked to Alzheimer’s disease [Tobinick 2008], recurrent ovarian cancer [Madhusudan, 2005], and autoimmune thyroid diseases [Wang, 2007].

In addition to cytokines and monocytes, platelets have also been shown to have a role in rheumatoid arthritis [Boilard 2010]. The regulated synthesis of interleukin 1β by activated platelets mediates inflammatory signaling [Lindemann, 2001]. Adhesion of platelets-neutrophil complexes in vivo contributes to acute inflammatory responses [Kornerup, 2010]. Platelet microparticles, which are submicrometer vesicles generated by activated platelets, have been found to induce the secretion of cytokines such as IL-1 by synovial fibroblasts [Boilard 2010]. Platelet-polymorphonuclear neutrophil (PMN) adhesion has been shown to contribute to inflammation [Pastakia, 1996]. The production of microparticles from the platelet membrane is activated via the collagen receptor GPVI [Boilard 2011]. In rheumatoid arthritis patients, high levels of microparticles in the synovial fluid stimulate the production of IL-1, thus increasing joint inflammation [Boilard 2011]. Research has shown that a raised platelet count is correlated to rheumatoid arthritis [Farr, 1983] and that this can be used to create functional assays that monitor disease activity [Gyorgy, 2011].

Platelets can also induce inflammatory responses in the synovial membrane of the joints in rheumatoid arthritis patients by a separate pathway that does not involve microparticles [Boilard, 2011]. Platelets interact with collagen and become activated by means of the platelet collagen receptor Glycoprotein IV [Smethurst, 2006]. Activated platelets express cyclooxygenase-1 (COX-1), which increases the paracrine production of prostacyclin in fibroblast-like cells called synoviocytes [Boilard, 2011].

The TNFα / NF-kB Biochemical Pathway

Tumor Necrosis Factor alpha (TNFα), a cytokine secreted by macrophages and monocytes, has been found to mediate the inflammatory response and the activation of apoptosis in cells in rheumatoid arthritis, among other diseases [Chen, 2002][ Baumgartner, 2000]. In rheumatoid arthritis patients, high levels of TNFα can be found in the synovial fluid, synovial tissue, and in the cartilage-pannus junction [Baumgartner, 2000]. IL-1 release triggered by TNFα has been linked experimentally to decreases in patient’s cognitive abilities [Terrando, 2010].

It is known that cytokines binding to transmembrane receptors causes an increase of tyrosine phosphorylation, which in turn triggers the activation of signal transduction pathways [Bracke, 1998]. TNFα interacts with two membrane-bound receptors, TNF-R1 and TNF-R2, with TNF-R1 being the one involved in the most important biochemical pathway for rheumatoid arthritis, the TNFα / NF-kB signal transduction pathway [Chen, 2002][Locksley, 2001].

When TNFα binds to TNF-R1, it activates a signal transduction pathway that leads to the activation of transcription factors NF-kB and c-Jun, which are involved in the transcription of genes related to cell death, immunological and inflammatory responses, and cancer, among others (Chen, 2002). Figure 2 illustrates the signal transduction pathway for TNFα / NF-kB.

When TNFα binds to the TNF-R1 membrane-bound receptor, the intra-cellular domain of the TNF-R1 receptor releases the SODD (silencer of death domain) inhibitory protein [Chen, 2002]. When this happens, the TNF receptor-associated death domain (TRADD) recognizes the change in the intra-cellular domain of TNF-R1 and recruits adaptor proteins such as receptor-interacting proteins (RIP), which is a protein kinase; TNF-R-associated factor 2 (TRAF2); and Fas-associated death domain (FADD)[Chen, 2002] [Locksley, 2001].

RIP, TRAF2 and FADD in turn recruit enzymes to the intracellular domain of TNF-R1 in order to initiate the signaling cascade [Chen, 2002]. FADD recruits caspase-8, TRAF2 recruits cIAP-1 and CIAP-2, and activates a cascade of kinases that results in the phosphorylation and activation of c-Jun [Chen, 2002].

NF-kB is normally found bound to inhibitor IkB proteins in the cytoplasm, which maintains it inactive [Chen, 2002]. The kinase cascade that phosphorylates and activates c-Jun also causes the phosphorylation and activation of the IKK (IkB kinase) complex, which mediates the phosphorylation of IkB proteins; this in turn causes IkB to disassociate from NF-kB [Chen, 2002]. Once NF-kB is separated from IkB, it becomes activated, and translocated into the nucleus of the cell, where it recruits other transcription factors and expresses genes related to apoptosis (cell death) and the inflammatory response [Chen, 2002].

Figure 2: TNFα / NF-kB signal transduction pathway (Chen, 2002)

NF-kB triggers the inflammatory response by promoting the transcription of genes that express inflammatory cytokines such as interleukin-1 (IL-1a and IL-β) [Dinarello, 1996]. IL-1 activates T-cells and enhances the proliferation of fibroblasts, which in turn causes the formation of the pannus and contributes to the destruction of bone, cartilage and joint tissues [Furst, 2004].

Other Relevant Pathways

Inhibiting the action of TNFα and IL-1 suppresses the symptoms of rheumatoid arthritis in many patients; however, in a large percentage of patients symptoms persist, indicating that there are alternate pathways involved in the mechanism of the disease [Walker, 2005]. In addition to the two platelet-related mechanisms mentioned previously, another pathway that has been proposed and investigated is the Jak-STAT signal transduction pathway [Walker, 2005].

Treatment of Rheumatoid Arthritis

The main purpose of pharmacological treatments for rheumatoid arthritis is to prevent joint damage, reduce the inflammatory response, and improve joint function [Hekmat, 2011].

There are three fundamental ways of inhibiting the biochemical pathways that trigger tissue inflammation and cell apoptosis: neutralizing the action of inflammatory cytokines (keep them from binding with their corresponding transmembrane receptors by binding the cytokines with a soluble receptor, a monoclonal antibody, or a natural antagonist), blocking the transmembrane receptors for inflammatory cytokines (use a receptor antagonist or a monoclonal antibody to bind to the receptor and blocking the cytokine from binding), and activating pathways that will express anti-inflammatory cytokines such as IL-4 or IL-10, which inhibit the expression of inflammatory cytokines [Chen, 2002].

On in-vitro studies performed on synovial cells from rheumatoid arthritis patients, inhibiting the action of TNFα had the effect of reducing the production of cytokines associated with inflammatory responses, such as IL-1, IL-6, and IL-8, among others [Chen, 2002]. This key role of TNFα makes it a prime target for drugs that inhibit its effect [Chen, 2002]. The TNF-R2 receptor fused with the human IgG1 Fc region has also been used to treat rheumatoid arthritis, but it is not as effective as other antibodies against cells with TNF on the cell surface [Nagashima 2011].

There are three main types of drugs used to treat rheumatoid arthritis: NSAIDs, DMARDs, and biologics [Shiel, 2011]. These are frequently used in combinations for best effect [Shiel, 2011]. In this paper, we will provide a general description of NSAIDs and DMARDs, and will focus on biologics and their mechanisms of action at the molecular level. This paper will further focus on the four biologic treatments most widely used against rheumatoid arthritis: Enbrel (Etanecerpt), Humira (Adalimumab), Kineret (Anakinra), and Remicade (Infliximab) [Cush, 2010].

NSAIDS

The first class of drugs used to treat rheumatoid arthritis are Non Specific Anti-Inflammation Drugs (NSAIDs) [Shiel , 2011]. NSAIDs are fast-acting drugs that treat the symptoms of rheumatoid arthritis such as pain, swelling, and inflammation [Shiel, 2011]. NSAIDs do not alter the course of the disease or slow down the progression of joint destruction [Shiel, 2011].

NSAIDs act as cyclooxygenase (Cox-1 and Cox-2) inhibitors [Silverstein, 2000]. These cyclooxygenase enzymes play a key role in the production of prostaglandines; by inhibiting their actions, NSAIDs reduce swelling and pain [Silverstein, 2000]. Cox-1 inhibition also causes gastrointestinal toxic effects, such as ulcers [Silverstein, 2000]. Celecoxib, which is a Cox-2- specific inhibitor, has been shown experimentally to cause lower gastrointestinal toxic effects than ibuprofen [Silverstein, 2000]. Table 1 lists the most commonly used NSAIDs.

NSAIDs
Generic name	Commercial Name
Acetylsalicylate	Aspirin
Naproxen	Naprosyn
Ibuprofen	Advil, Medipren, Motrin
Etodolac	Lodine
Cox-2 inhibitors, such as Celecoxib	Celebrex

Table 1 : NSAIDs used in the treatment of rheumatoid arthritis (Shiel, 2011)

DMARDS

The second class of drugs used to treat rheumatoid arthritis are Disease Modifying Anti Rheumatoid Drugs (DMARD) [Shiel, 2011]. DMARDs slow down the progression of the disease, but they act slower than NSAIDs; their effect becomes observable weeks or months after the patient starts to take them [Shiel, 2011]. Table 2 lists the most commonly used DMARDs.

A research study performed by Mottonen, et al [1999] compared combination therapies consisting of various DMARDs such as sulphasalazine, methotrexate, hydroxy-chloroquine, and prednisolone, against a single-drug therapy. Combination therapy showed significant improvements in swollen joint count over the single-drug treatment [Mottonen, 1999]. In some patients, however, DMARDs do not attain satisfactory responses due to toxicity [Moreland, 1999].

Another research study, performed by Cohen [2001] compared the effects of treating rheumatoid arthritis with leflunomide against the effects using methotrexate, in a two-year-long, randomized, controlled clinical trial. Both treatments slowed down the progression of the disease, with leflunomide showing better results than methotrexate [Cohen, 2001].

A more recent research study performed by DeStefano [2010] compared combination therapies of leflunomide plus an anti-TNFα biologic against methotrexate plus an anti- TNFα biologic. The study shows that both DMARDs can be used safely in combination with anti- TNFα biologics [DeStefano, 2010].

DMARDs
Generic name	Commercial Name
Hydroxychloroquine	Plaquenil
Sulfasalazine	Azulfidine
Leflunomide	Arava
Gold salts such as Gold thioglucose Gold thiomalate Oral gold, auranofin	Solganal Myochrysine Ridaura
D-penicillamine	Depen, Cuprimine
methotrexate	Trexall
azathioprine	Imuran
cyclophosphamide	Cytoxan
chlorambucil	Leukeran
cyclosporine	Sandimmune

Table 2 : DMARDs used in the treatment of rheumatoid arthritis (Shiel, 2011)

Biologic treatments for Rheumatoid Arthritis

A third class of drugs used to treat rheumatoid arthritis are Biologics. While DMARDs are non-specific anti-inflammation drugs that target the immune system in a general way [Shiel, 2011], most biologics target specific cell surface markers or specific signaling molecules to inhibit their action and prevent the triggering of biochemical pathways that lead to inflammation responses and apoptosis [Rasheed 2008]. Table 3 lists various biologic drugs used to treat rheumatoid arthritis.

The current treatment approach is to combine use of DMARDs and biologics at the early stages of the disease to achieve complete remission [Dudler, 2011]. Klareskog [2004] compared a combined treatment of rheumatoid arthritis patients using etanercept and methotrexate (DMARD) against treatment with each alone, using a double-blind randomized trial. The combined treatment reduced symptoms, improved patient’s functional disabilities, and slowed down the disease’s progression. [Klareskog, 2004].

Biologics
Generic name	Commercial Name
Etanercept	Enbrel
Infliximab	Remicade
Anakinra	Kineret
Adalimumab	Humira
Rituximab	Rituxan
Abatacept	Orencia
Golimumab	Simponi
Certolizumab pegol	Cimzia
Tocilizumab	Actemra

Table 3 : Biologics used in the treatment of rheumatoid arthritis (Cush, 2010)

A study performed by Graudal, et al [2010] in the Netherlands showed that biologics, glucocorticoids, DMARDs, and combined agents had similar effects on patients after one year of treatment; which led these researchers to recommend that biologics should be used only for patients that are not responsive to DMARDs treatments [Graudal, 2010].

Combination therapy using multiple biologic drugs has not demonstrated any synergistic effects; in a study that combined the use of Etanercept, a TNFα inhibitor, with Anakinra, an IL-1 inhibitor, patients did not gain any additional benefits, while the risk of serious infections increased significantly [Genovese, 2004].

As mentioned previously, this paper will focus on the four biologic treatments most widely used against rheumatoid arthritis: Enbrel (Etanecerpt), Humira (Adalimumab), Kineret (Anakinra), and Remicade (Infliximab) [Cush, 2010].

Etanercept (Enbrel)

Etanercept , which is sold under the commercial name Enbrel, is a recombinant dimeric fusion protein, which combines the human gene for the extracellular ligand-binding domain of two human soluble TNFα type-II receptors with the gene for the Fc (fragment crystallizable) component of human immunoglobulin G1 (IgG1) [Tobinick 2008] [Wikipedia: Etanercept, 2011]. It inhibits TNFα by binding to it, which prevents it from binding to transmembrane receptors [Cush, 2010]. It has a half life of 5 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how soluble receptors such as Enbrel bind to cytokines to inhibit their action.

The most common adverse effects observed in Enbrel patients are injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Less common adverse effects observed are bacterial infections, optic neuritis, multiple sclerosis, nerve disorders, and heart failure [Cush, 2010].

Figure 3: Inhibition of Cytokines by binding with monoclonal antibodies or soluble receptors (Choy, 2001).

Enbrel is administered by subcutaneous injection, once or twice per week [Cush, 2010]. FDA prescription guidelines do not require using methotrexate along with Enbrel [Cush, 2010]. The dose is 50 mg weekly, or 25 mg twice per week [Cush, 2010]. The estimated annual cost of treatment is $15,436 [Cush, 2010].

In clinical trials, Enbrel has been shown to reduce symptoms of rheumatoid arthritis, to slow down the progression of joint damage, and to improve the general quality of life in patients [Moreland, 1999][Haraoui 2007]. A clinical trial was performed by Johnsen, et al [2006] to determine the effects of a dosing regimen of 50 mg twice weekly, twice the current regime. No increase in effect or benefits to patients were observed at the higher dose, when compared to the current dose [Johnsen, 2006].

Etanercept has also been evaluated as a treatment for Alzheimer’s disease [Tobinick 2008] and recurrent ovarian cancer [Madhusudan, 2005]. Excessive amounts of TNFα, which has been found to regulate synaptic functions in neural networks, have been linked to Alzheimer’s disease [Tobinick 2006]. Alzheimer’s patients treated with Enbrel showed rapid cognitive improvements within minutes of receiving the drug [Tobinick 2008]. TNFα , as a major mediator of inflammation, is produced chronically in ovarian tumors, and the increase in cytokine production triggered by TNFα is believed to assist in tumor growth [Madhusudan, 2005]. The Madhusudan study found evidence of biological activity of etanercept against ovarian cancer, and recommended further research [Madhusudan, 2005].

Adalimumab (Humira)

Adalimumab , which is sold under the commercial name Humira, is a fully-human monoclonal antibody [Wikipedia: Adalimumab, 2011] that binds to TNFα and inhibits it from binding to transmembrane receptors. [Cush, 2010]. It has a half life of 12-14 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how monoclonal antibodies bind to cytokines to inhibit their action.

The most common adverse effects observed in Humira patients are similar to those observed in Enbrel patients: injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Less common adverse effects observed are bacterial infections, optic neuritis, multiple sclerosis, nerve disorders, and heart failure [Cush, 2010].

Humira is administered by subcutaneous injection, every other week [Cush, 2010]. FDA prescription guidelines suggest using methotrexate along with Humira [Cush, 2010]. The dose is 40 mg once every two weeks[Cush, 2010]. The estimated annual cost of treatment is $14,522 [Cush, 2010].

In clinical trials, Adalimumab has been shown to be safe and effective in the treatment of rheumatoid arthritis and other inflammatory conditions both in monotherapy [van de Putte, 2003], and in combination therapy with methotrexate [Breedveld, 2006][Weinblatt, 2003]. Combination therapy was found to be more effective than monotherapy [Breedveld, 2006].

Anakinra (Kineret)

Anakinra, which is sold under the commercial name Kineret, is a receptor antagonist [Wikipedia: Anakinra, 2011] [Furst, 2004] that inhibits the effect of Interleukin-1 (IL-1) by competitively inhibiting the binding of IL-1 to the IL-1 transmembrane receptors [Schiff, 2000][Cush, 2010]. It has a half life of 6 hours [Cush, 2010]. Effects on most patients can be seen 4 - 6 weeks after the treatment begins [Cush, 2010]. Figure 4 shows how receptor antagonists such as Anakinra bind to transmembrane receptors to inhibit the action of cytokines.

The most common adverse effects observed in Kineret patients are similar to those observed in Enbrel and Humira patients: injection site reactions such as skin irritation, and upper respiratory infections such as cold, sinusitis, or bronchitis [Cush, 2010]. Headaches are also a common adverse effect of Kineret, not observed in other biologics [Cush, 2010]. Less common adverse effects observed are pneumonia, skin or joint infections, and very low white blood cell counts [Cush, 2010].

Kineret is administered by subcutaneous injection, daily [Cush, 2010]. FDA prescription guidelines do not require using methotrexate along with Kineret [Cush, 2010]. The dose is 100 mg daily [Cush, 2010]. The estimated annual cost of treatment is $12,800 [Cush, 2010].

Figure 4: Blocking of transmembrane receptors by binding with monoclonal antibodies or receptor antagonists (Choy, 2001)

In clinical trials, Anakinra has been shown to be mildly to moderately effective in reducing symptoms of active rheumatoid arthritis in patients, both in monotherapy [Fleischmann, 2003] and combined with methotrexate [Furst, 2004].

Infliximab (Remicade)

Infliximab, which is sold under the commercial name Remicade, is a mouse-human chimeric antibody [Wikipedia: Remicade, 2011] that inhibits the action of TNFα by binding to it [Cush, 2010]. It has a half life of 9 days [Cush, 2010]. Effects on most patients can be seen 2 - 4 weeks after the treatment begins [Cush, 2010]. Figure 3 shows how monoclonal antibodies bind to cytokines to inhibit their action.

The most common adverse effects observed in Remicade patients are infusion reactions such as itching, rash, nausea, and headaches; and upper respiratory infections such as cold, bronchitis, and sinusitis [Cush, 2010]. Less common adverse effects observed are anaphylaxis; opportunistic bacterial infections such as pneumonia or joint infections; tuberculosis; fungal infections; nerve disorders such as optic neuritis and multiple sclerosis; and worsening of heart failure [Cush, 2010].

Unlike Enbrel, Kineret or Humira, which are self-administered by subcutaneous injection, Remicade is administered by intravenous infusion in the clinic or doctor's office, every 8 weeks [Cush, 2010]. FDA prescription guidelines require using methotrexate along with Remicade [Cush, 2010]. The initial dose is 3 - 5 mg/kg at weeks 0, 2, and 6; and if necessary this dose can be increased to 5 - 10 mg/kg [Cush, 2010]. Maintenance doses are required every 4 - 8 weeks [Cush, 2010]. The estimated annual cost of treatment is between $13,940 and $30,287 [Cush, 2010].

Clinical trials have compared monotherapy with Infliximab against monotherapy with methotrexate, and against a combined therapy of both Infliximab and methotrexate [StClair, 2004][Maini, 1998]. It was found that the combined therapy is more effective than monotherapy with either drug alone [StClair, 2004] [Maini, 1998]. However, other studies in Infliximab patients showed poor response, prompting the physicians to switch patients to other treatments [Mori 2011].

Investigational Drugs

According to ClinicalTrials.gov, a website maintained by the National Institutes of Health (NIH), there are eleven drugs for the treatment of rheumatoid arthritis currently undergoing clinical trials; as shown in Table 4.

Drug	Sponsor	Stage
CP-690,550	Pfizer	III
Biological: Certolizumab Pegol	UCB i	III
PPAR-Gamma Agonists	University of Michigan / NIH	III
Ocrelizumab	Roche	III
CRx-102	CombinatoRx	II
Apremilast	Baylor Research Institute	II
SCIO-469	Scios, Inc.	II
Tranilast	Imperial College London	I
ACZ885 Canakinumab	Novartis	I
SBI-087	Wyeth	I
Cura-100	Cura Biotech LLC	I

Table 4 : Rheumatoid drugs currently in clinical trials

Proposed Drug

Laliumab, which will be sold under the commercial name Jazireum®, is a fully human monoclonal antibody that treats autoimmune disease by blocking the active site of the Tumor Necrosis Factor Receptor-1 (TNF-R1) transmembrane protein. Figure 5 shows a computer rendition of the Lalitumab protein molecule model, obtained using X-Ray crystallography, WinCoot, and Swiss PDB Viewer.

Figure 5: Laliumab (Jazireum®), a fully human monoclonal antibody
(source: http://mimetibody.com/)

Mechanism of Action

Laliumab disrupts the interaction between TNFα and the TNF-R1 transmembrane receptor by blocking the active site of the receptor, and thus inhibiting TNFα from binding. By binding competitively with the TNF-R1 receptor (Figure 6), Laliumab prevents the formation of the TNFα-TNF R1 complex, and this in turn prevents the triggering of the pathway which produces cell necrosis and inflammation in rheumatoid arthritis and other autoimmune diseases.

Adverse Events

As with other anti-TNFα biologics, the main adverse events associated with Laliumab are injection site reactions such as irritated skin, and opportunistic infections in the respiratory tract, such as cold, sinusitis, and bronchitis.

Less common adverse events are also similar to those caused by other anti- TNFα biologics: opportunistic bacterial infections; nerve disorders such as seizures, multiple sclerosis, and eye nerve inflammation; psoriasis; allergic reactions; autoimmune reactions; and heart failure.

Formulation, Dose, and Cost Estimate

Laliumab is self-administered by subcutaneous injection. It is available in two dosage options: a 50 mg/mL autoinjector, and a 50 mg single-use prefilled syringe.

Laliumab has a half-life of approximately 12-14 days. Most patients will begin to feel effects within 2 – 4 weeks after the start of the treatment. FDA prescription guidelines suggest using Laliumab along with methotrexate for optimal effect. The estimated annual cost of treatment is $15,000.

Figure 6: Laliumab blocks the action of TNFaby binding to the TNF-R1 receptor active site

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2. Chen G & Goeddel D. TNF-R1 Signaling: A Beautiful Pathway. Science May 2002; 296; 1634-1635.

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4. Dinarello C, Biologic Basis for Interleukin-1 in Disease . Blood 1996; 87: 2095-2147

5. Dudler J, et al. Biologics in Rheumatoid Arthritis (RA)- Recommendations for Swiss Practice. Swiss Med Wkly. 2001; 141:w3189.

6. Firestein G. Evolving Concepts of Rheumatoid Arthritis. Nature. May 2003; 423:356-361.

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8. Locksley R, et al. The TNF and TNF Receptor Superfamilies: Integrating Mammalian Biology. Cell. 2001; 104:487-501.

9. McCoy M, Tansey M, TNF Signaling Inhibition in the CNS: Implications for normal brain function and neurodegenerative disease. Journal of Neuroinflammation 2008; 5:45

10. Perricone C, et al. An Overview on the Genetic of Rheumatoid Arthritis: A Never-Ending Story. Autoimmunity Reviews; 2011.

11. Rasheed Z and Haqqi T, Update on Targets of Biologic Therapies for Rheumatoid Arthritis. Current Rheumatology Reviews, 2008, 4, 246-253.

12. Tobinick E & Gross H. Rapid Cognitive Improvement in Alzheimer’s Disease Following Perispinal Etanercept Administration. Journal of Neuroinflammation 2008, 5:2

13. Walker J and Smith M. The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 2005;32;1650-1653.

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