Biologic Therapies in Rheumatoid Arthritis

 

Reumatol Clin. 2010;6(1):23–36

Volumen 6,Número1

Editoriales

Genéticadel Lupuseritematoso generalizado NewDrugsfor Rheumatoid Arthritis:  The IndustryPointof View 

Originales

Hiperlaxitud ligamentosaen población escolar Dañoen pacientescubanoscon lupus eritematososistémico Fibromialgia:percepción de pacientes sobre su enfermedad  Actualización ConsensoSERde terapiasbiológicasen AR 

Revisiones Estrategiasterapéuticasen el síndrome antifosfolipídico Fármacosen el embarazoycontracepción en enfermedadesreumáticas

 Artículo especial

Gripe A:RecomendacionesSER 

Resonancia deraquiscompleto (págs.49-52)

www.reumatologiaclinica.org

Original article

Update of the Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in rheumatoid arthritis  Jesús Tornero Molina,a Raimon Sanmartí Sala,b Vicente Rodríguez Valverde,c Emilio Martín Mola,d   José Luis Marenco de la Fuente,e Isidoro González Álvaro, Álvaro,f  Santiago Muñoz Fernández,g   Juan Gómez-Reino Carnota,h Luis Carreño Pérez,i Enrique Batlle Gualda, j Alejandro Balsa Criado,d   José Luis Andreu, Andreu,k José María Álvaro-Gracia,f  Juan Antonio Martínez López,f,l and Estíbaliz Loza Santamaría,l,* a Servicio

de Reumatología, Hospital General de Guadalajara, Guadalajara, Spain de Reumatología, Hospital Clínic i Provincial, Barcelona, Spain c Servicio de Reumatología, Hospital Marqués de Valdecilla, Santander, Spain d Servicio de Reumatología, Hospital La Paz, Madrid, Spain e Servicio de Reumatología, Hospital de Valme, Sevilla, Spain f  Servicio de Reumatología, Hospital de la Princesa, Madrid, Spain g Servicio de Reumatología, Hospital Infanta Sofía, Madrid, Spain h Servicio de Reumatología, Hospital General de Santiago, Santiago de Compostela, A Coruña, Spain b Servicio

i  j Servicio  Servicio

de Reumatología, Hospital Gregorio Marañón, Madrid, Spain de Reumatología, Hospital General de Alicante, Alicante, Spain k Servicio de Reumatología, Hospital Puerta de Hierro, Madrid, Spain l Unidad de Investigación, Sociedad Española de Reumatología, Madrid, Spain

ARTICLE

  INFO

 Article history:

Received October 15, 2009 Accepted October 26, 2009 Available online December 6, 2009 Keywords:

Consensos Recommendations Guidelines Biologic therapies Rheumatoid arthritis

ABSTRACT

Objective: To provide a reference to rheumatologists and to those involved in the treatment of RA who are

using, or about to use biologic therapy. Methods:   Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established established through Delphi technique. Results: We have produced recommendations on the use of the seven biologic agents available for RA in our country. The objective of treatment is to achieve the remission of the disease as quickly as possible. Indications and nuances regarding the use of biologic therapy were reviewed reviewed as well as the evaluation that should be performed prior to administration and the follow up of patients undergoing this therapy. Conclusions:  We present an update on the SER recommendati recommendations ons for the use of biologic therapy in patients with RA. © 2009 Elsevier España, S.L. All rights reserved.

 Actualización del Documento de Consenso de la Sociedad Española de Reumatología sobre el uso de terapias biológicas en la artritis reumatoide RESUMEN

Palabras clave:

Consenso Recomendaciones Guías Terapias biológicas Artritis reumatoide

Objetivo: Servir de referencia para reumatólogos e implicados en el tratamiento de la artritis reumatoide que vayan a utilizar o consideren la utilización de terapias biológicas en su manejo. Métodos: Las recomendaciones se emitieron siguiendo la metodología de grupos nominales y basadas en revisiones sistemáticas. El nivel de evidencia y el grado de recomendación se clasificaron según el modelo del Center for Evidence Based Medicine de Oxford y el grado de acuerdo se extrajo por técnica Delphi. Resultados: Se realizan recomendaciones sobre el uso de los siete agentes biológicos disponibles para la artritis reumatoide en la actualidad en nuestro país. El objetivo del tratamiento es lograr la remisión de

* Corresponding author. E-mail address: estibaliz.loza@ser [email protected] .es (E. L oza Santamaría). 1699-258X/$ - see front matter © 2009 Elsevier España, S.L. All rights reserved.

 

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la enfermedad lo más precozmente posible. Se revisan las indicaciones y matizaciones del uso de terapias biológicas y cuál debe ser la evaluación previa y la vigilancia del paciente con estos fármacos. Conclusiones:  Se presentan las actualiza actualizaciones ciones a las recomendaciones SER para el uso de terapias biológicas en pacientes con artritis reumat reumatoide. oide. © 2009 Elsevier España, S.L. Todos los derechos reservados.

Introduction

Rheumatoid Arthritis (RA) is a disease characterized by chronic inflammation of the joints, affecting 0.5% of the adult population in Spain.1 In most of the cases, its course is progressive and leads to irreversible joint damage, which in turn causes patient disability, a reduction in the quality of life and premature mortality. However, However, the past few years have shown advances of great impact in the treatment of the disease, which contributes to the modification of this somber analysis. The treatment of RA is directed toward controlling inflammatory activity, avoiding progression of the joint structural lesion and preventing patient disability. Although non-steroidal antiinflammatory drugs provide symptomatic relief, their efficacy is marginal at best and treatment is based on the use of the so-called disease-modifying anti-rheumatic drugs (DMARD). These are the only agents proven, though controlled trials, to act against the different manifestations of RA. There are two groups of drugs that reunite these characteristics: traditional DMARD and biologic therapy. The first are a group of small synthetic molecules, with an occasionally poorly defined mechanism of action or with a therapeutic target that is not precisely that which is involved in the pathogenic immune response process. In this document, the term DMARD specifically refers to this type of medication. Biological therapies are, according to the European Drug Agency (EDA), products used for the treatment of diseases elaborated from cultured cells in cell banks. With the exception of microbial metabolites such as, for example, antibiotics, carbohydrates and other low molecular weight compounds. These therapies have been designed in a manner that acts specifically against a therapeutic target considered as important for a disease pathogenic process. One of the greater advances produced in the past years regarding RA is the modification of the therapeutic strategy. The

and help in therapeutic decision making processes. This document should also serve as reference both to rheumatologists as well as all those, be it from some other position, involved in the treatment of RA. Methods

To carry out this consensus, we used a modification of the RAND/ UCLA7 methodology. Nominal groups were created and Delphi surveys were carried out, as well as systematic reviews of controversial recommendations. A panel of experts on RA was created based on the following criteria: 1) that they had published articles on RA, and 2) that the articles were published in MEDLINE, Reumatología Reumatología Clínica or Revista Española de Reumatología. The members of the panel received a dossier with the previous consensus, GUIPCAR and all of the new clinical trials published from January 2006 until November 2008 with the GUIPCAR search strategy for clinical RA trials. Two meetings of the nominal group were carried out and moderated by members of the research unit of the Spanish Society of Rheumatology. In the first meeting, proposals of modification of the 2006 8  updated document were elaborated and discussed, and a Delphi survey based on this modifications was applied. With the results of the Delphi survey, the most controversial recommendations, and those of greater interest for the consensus were decided upon. From this point, members of the panel carried out questions that could be answered through a systematic review. In the second meeting, results of the systematic review were presented, all of the modifications were discussed again and consensus recommendations were generated. Lastly, the degree of agreement of the recommendations was evaluated and the definite document was written. The degree of agreement was defined as the percentage

two key elements in thistherapeutic change are objective, the early use of as DMARD and establishing a concrete such achieving 2-4 remission or a low degree of disease activity.   This has been proven to have as much importance as the drugs employed in order to achieve it.5 The application of these new strategies, along with the availability of an ever-greater number of biologic agents, has sensibly improved our capacity to induce remission in many patients with RA and to significantly modify its progression in others. However, it must be taken into account that even the new biologic agents do not achieve a necessary response in 40%-50% of patients, and they tend to lose efficacy with time.6  This makes it essential to have them all in a therapeutic arsenal for this disease. The high cost of these drugs and the still scarce information on their long-term safety forces their rational use. Therefore it is advisable to integrate their use within an integral therapeutic strategy for the disease.

of consensus between obtainedsurvey. by voting on each recommendation throughpanelists an anonymous The degree of evidence and recommendation were classified according to the Center for Evidence Based Medicine de Oxford model.9

The present(SER) Consensus Document Spanishpublished Society in of Rheumatology is an update on the of lastthe document 2006.. Its recommendations are centered on the treatment of RA with 2006 biologic agents in adults. The intention of these recommendations is not to serve as a treatment protocol but to improve assistance care

contraindications and not adverse events. This opinion does exclude the use of other DMARD such as sulphasalazine, antimalarials (cloroquine and hydroxicloroquine), cyclosporine, aurothyomalate sodium or azathioprine, but their use is not to be considered as necessary before installing biologic therapy.

Prior considerations Doses and guidelines recommended for the most relevant DMARD

Although all of the DMARD have shown to be effective to a greater or lesser degree in controlled studies, the panel considers, as the most relevant DMARD, taking into account their speed of action, clinical efficacy, influence on the progression of radiological lesions and tolerance, methotrexato methotrexato (MTX) and leflunomide (see GUIPCAR 10). Doses and guidelines for the use of these two drugs as recommended by the panel appear summarized in Table 1, along with the main

 

 

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 Table 1

Main disease modifying anti-rheumatic drugs (DMARD) according to the drug insert unless otherwise specified  Active ingredient

Dose and form of administration

Indications

Contraindications

Adverse events*

 Leflunomide  

– Dose: 10-20 mg – Via: orally – Frequent: daily. Start with 100 mg/day for 3 days, or start directly without loading dose

– Active RA

– Allergy to active ingredient or vehicle – Liver failure, severe infection, severe immunodeficiency, important cytopenia, moderate/severe moderate/severe renal failure, severe hypoprotei hypoproteinemia nemia – Pregnancy and lactation

– Very frequent: not mentioned in insert – Frequent: leukocytopenia, nausea, diarrhea, oral ulcers, tenosynovitis, ↑ transaminases, ↑ creatinphosphokynase, headache – Infrequent: rash, anxiety, anemia – Rare: pancytopenia, interstitial lung disease, hepatitis, severe hypertension, pancreatitis

– Dose: 7.5-25 mg – Via: orally or parenteral – Frequency: weekly weekly.. Start at 7.5-100 mg/week for 4 weeks and 7.5-1 ↑ 2.5-5 mg every 2-6 weeks – Administer folic acid 5-10 mg/week – Adjust dose if renal failure present – If oral route is ineffective, parenteral dose might be considered

– Active RA

– Allergy to the active ingredient or vehicle – Chronic liver disease, alcoholism, liver failure, severe renal failure, blood abnormalities, immunodeficiency – Pregnancy and lactation

– Very frequent: stomatitis, nausea, ↑ transaminases – Frequent: oral ulcers, headache, anemia, leucocytopenia, thrombocytopenia, pneumonitis – Infrequent: lymphoma, ↑ rheumatic nodules, cirrhosis, liver fibrosis – Rare: sepsis, neoplasia, renal failure, lung fibrosis

 

 Methotrexate      

RA: rheumatoid arthritis. Data obtained from Vademecum, GUIPCAR, EMEA, MSC and Cochrane library. * Adverse events: very frequent (at least once every 10 patients); frequent (once every 100 patients); infrequent (at least once every 1,000 and less than once every 100); rare (at least once every 10,000 and less than once every 1,000 patients).

We currently have seven biological agents available for the treatment of RA: three against tumor necrosis factor (anti-TNF)—a fusion protein with the soluble receptor etanercept (ETN) and two monoclonal antibodies, infliximab (IFX) and adalimumab (ADA)—, an interleukin inhibitor (IL) 1—anakinra—, a monoclonal antibody against B lymphocytes—rituximab (RTX)—, a modulating fusion protein for T cell activation—abatacept (ABA)—, and a monoclonal antibody vs. the IL-6 receptor—tocilizumab (TCZ). Table 2 summarizes the main characteristics of these agents. The three anti-TNFs, anakinra and TCZ are approved approved in Spain as a first line biologic in patients with DMARD failure, while RTX and ABA are approved for patients after failing to anti-TNF.

weekly).15,17,19 Therefore, when administering anti -TNF, combination with MTX is currently the most appropriate way, unless the patient has presented toxicity or intolerance related to the latter drug. There are no controlled studies that demonstrate that the combination with a DMARD different from MTX and anti-TNF improves their efficacy. However, it is frequent practice that, in patients with intolerance to MTX, anti-TNF is combined with a different DMARD, especially leflunomide.20 Curiously, in a controlled study, combined treatment with sulphasalizine and ETN was not more effective than monotherapy monothera py with ETN after 6 months,21 but after 2 years there were differences in favor of the combination, at least regarding the DAS.22 Another available agent, anakinra, the human recombinant form of the IL-1 receptor antagonist, has shown efficacy vs. placebo, both in symptom improvement of RA as for radiological progression. 23  Although it has never been compared in controlled studies with other biologics, there is a generalized perception that their efficacy is inferior to that of anti-TNFs. On the other hand, it is interesting

In controlled ofthree RA patients andespecially an insufficient to DMARD, mainly studies MTX, the anti-TNFs, whenresponse combined with MTX, are superior to this drug employed as monotherapy, monotherapy, both from the clinical activity and radiological progression standpoint standpoint..12-14  In addition, controlled studies in patients with early RA have shown that its treatment with any anti-TNF, especially if combined with MTX, is capable of inducing remission in a sizable proportion of patients, as well as avoiding the development of radiological lesions or stopping its progression to a greater degree than MTX alone.15-17  There is no data that confirms the superiority of one anti-TNF over another, making the concrete decision on which one to use dependent on the physician’s criteria and each patients particular circumstances. However, attention must be called upon their particular structure, antigenicity and mechanism of action, making the lack of response to one not necessarily a factor in the response to any other. In this sense, there is data that suggests that patients that have not responded to an anti-TNF may satisfactorily

to point out thatresponse Still’s disease, bothorinanti-TNF childrenis and adults, in which sometimes to DMARD unsatisfactory, uncontrolled observations indicate good, or even excellent response with anakinra.24,25 RTX is a chimerical monoclonal antibody directed specifically against CD20, a molecule that is expressed selectively on the surface of B cells; this drug produces selective and prolonged depletion of this type of lymphocyte. This agent has shown efficacy both in patients that have failed to respond to DMARD26 (although it has not been approved as a first line biologic agent) as in patients with an insufficient response to anti-TNF anti-TNF..27 In this sense, RTX is currently the only biologic with a demonstrated impact on structural damage in patients with an incomplete response to anti-TNF.28 It has recently been shown that in early RA patients, RTX in combination with MTX is superior to MTX as monotherapy. 29 However, such an indication is not approved in Europe. ABA is a fusion protein constituted by the CTLA4 receptor fused

18 respond another.  Therefore, panel considers Although that the three anti-TNFstoare necessary and nottheinterchangeable. ADA and ETN can be employed as monotherapy, controlled, double blind studies with these two drugs indicate that they are more effective when administered along with MTX at an adequate dose (15-20 mg

with a human IgG, with inhibiting binding B7 with CD80 for andT therefore interfering the sothe called secondofsignal necessary cell activation. In controlled studies with this agent it has shown, in patients with an incomplete response to MTX, that the combination with ABA is superior from a clinical and radiological standpoint to

Doses and guidelines recommended for these drugs can be consulted in GUIPCAR.11  Available  Ava ilable agents in biologic thera therapy py

 

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monotherapy with monotherapy wi th MTX 30 (however  (however,, ABA is not approved as first line therapy in Europe). In patients with incomplete response to anti-TNF anti-TNF,, ABA combined with MTX has been shown to be clinically superior to MTX monotherapy.31 TCZ, a humanized monoclonal antibody vs. the IL-6 receptor is the latest biologic agent available in Spain for the treatment of RA. A wide program of studies in phases II and III have shown the usefulness of this drug in different profiles of patients with RSA. In fact, TCZ has shown efficacy in patients unresponsive to DMARD,32,33   as well as in patients who had not yet received MTX 34  and in those that had responded inadequately to antiTNF. 35  TCZ is the only biologic agent that has proven superior to MTX as monotherapy.34   This has been proven both for clinical manifestations as well as in the delay of the progression of radiological damage.36-38 Clinical, functional and radiological evaluation of rheumatoid arthritis

In the standardized evaluation of RA it is recommended that the following measures be used (evidence level [EL] 1b; degree of recommendation [DR] A; degree of agreement [GA] 86.1%):  Activity::  Activity

Number of painful (NPJ) and swollen joints (NSJ). Global disease assessment by the patient and the physician (scale of 0 to 100).   Acute phase reactants (ESR, (ESR, CRP).

● ●

●

Structural damage: any radiological evaluation that includes the hands and feet, yearly for the first 3-4 years of the disease or when starting treatment with biologic agents. Function: HAQ 39 or other questionnair questionnaires, es, at least once a year. The systematic gathering of recommended variables allows for the calculation of the different indexes that have been validated to perform an objective estimate of disease activity: DAS, DAS28, SDAI, CDAI.40-44 The first two are based on four of the six previously mentioned variables: NPJ and NSJ (on 66/68 or 28 joints respectively), respectively), ESR and the global assessment of disease as performed by the patient. SDAI uses all of the variables with CRP as an acute phase reactant (not included in CDAI), but does not ponder each variable. Although the panel recommends the periodic evaluation of radiological progression in hands and feet, it is evident that, depending on the pattern of joint affection of each patient, those x-rays that are considered as necessary should also be carried out

with similar periodicity. Each therapeutic decision should be preceded by an objective evaluation of disease activity, preferably using DAS28 and/or SDAI or, in its absence, by documenting one of the components of those indexes. The evaluation has to be performed at least every three months if the therapeutic objective has not been reached and at least every 6 months once it has been achieved (EL, 5; DR, D; DA, 84.6%). Although any of the validated indices can be used to monitor the activity of RA, experts consider that the joint counts necessary necessar y to calculate the classic DAS are to extensive to be carried out in daily clinical practice. On the other hand, having a cutpoint for DAS28 and SDAI allows for a more objective vision than that of an isolated evaluation of its components. Therefore it is considered that DAS28 and SDAI are the ideal indices to evaluate the therapeutic objective, although the use of other validated indices is not discouraged. Therapeutic objective in rheumatoid arthritis

The panel considers that currently the idea of curing RA is a utopia and the objective of treatment should be achieving disease remission.

Although this concept is well known to rheumatologist rheumatologists, s, the objective description of this state of remission is controversial. Most of the proposed definitions of remission are based on clinical parameters, but in the past few years ecography and magnetic resonance have manifested that patients who clinically could be classified as in remission presented synovitis evident with these imaging techniques. However, due to the small amount of evidence that reflects the impact of these findings and the lack of standardization and generalization of these resources, the panel opted for a clinical definition of remission. Remission is defined as reaching any of the limits established for each one of the compared disease activity indexes such as DAS28<2.6 or SDAI<5 (LE, 1b; DR, A; DA, 83.1%). The fact that the cutpoint employed in order to define remission through DAS28 is a mere mathematical transformation of the estimate of the original DAS is an inconvenience that must be taken into account. This has led other authors to propose different remission cutpoints for the DAS28 than those suggested by Nijmegen,45  which waver between 3.5 and 2.4.46,47  In the case of SDAI, different cutpoints have also been suggested, oscillating between 3.3 and 5. 43,44 The therapeutic objective is to achieve remission of the disease, or instead, a low degree of disease activity, quantitatively defined through contrasting the cutpoints of activity, such as DAS28<3.2 or SDAI<11. The therapeutic objective is not considered as reached if, in spite of a low degree of activity there is persistent inflammation, unresolved with local therapeutic measures, in important joints for the patient or significant progression of radiological lesions (LE, 1b; DR, A; DA, 93.1%). Some practical considerations must be taken into account when applying disease activity indexes to individual patients: 1) women and patients with longer time since onset of disease have greater values of DAS 28 due to greater ESR 46,48-50 ; 2) other variables such as TJC51,52 or the global evaluation of disease can also bias the result of DAS28and SDAI, particularly the former, where painful joints are weighed much higher than swollen ones, and  3) in the case of SDAI, CRP values are not normalized and in some cases can lead to excessively excessiv ely high SDAI scores. Therefore, the panel considers that, in patients who have reached these generic improvement parameters but persist with inflammation in some important joint, or significant progression is detected on x-rays, the therapeutic objective would not have been reached and a change in treatment would be indicated. Considerations on the initial treatment of rheumatoid arthritis

There is evidence that intensive and early treatment of RA improves its progression, making it necessary to start DMARD treatment as soon as possible (LE, 2b; DR, B; DA, 96.2%). Evidence suggests that early and energetic therapy lead to better results.2,3,53,54   In fact, the response and evolution of disease after treatment, started at 3 months, is much higher than that obtained when this is delayed d elayed to 12 months.3 Therefore, the need for installing DMARD treatment as soon as the diagnosis of RA has been reached is well established. The greatest objection to early DMARD treatment is the possibility of treating a patient with transient polyarthritis polyarthritis as RA; but in any case, polyarthritis lasting more than 12 or 14 weeks has a high probability of persisting. Therefore, even when the American College of Rheumatology (ACR) criteria for RA are not met, faced with a high probability of being faced with early onset RA, the panel considers that treatment with DMARD should be started in these patients. Treatment of RA (NSAID and/or steroids and DMARD) in its initial phase needs frequent adjustment, making it necessary to monitor the patient frequently. The objective is to: 1) reach the therapeutic

 

 

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objective as soon as possible, and 2) rapidly identifies cases resistant to initial treatment. Initial treatment must include one of the relevant DMARD, of which MTX is a good example. MTX has to be administered in rapid increments until a dose of 15-20 or even 25 mg a week is reached in 8 weeks if there is no good clinical response. There is evidence that strict monitoring in the initial phase of RA is capable of inducing remission in an elevated percentage of patients 4,5; all of this leads to less disability in the medium and long terms and, therefore, to a reduction in the severe consequences of this process. In patients with an insufficient response or intolerance to MTX, leflunomide is an alternative. The use of sulphasalazine in Spain has traditionally been low.55  It is very likely that this is due in part to the fact that the Spanish formulation lacks enteric protection and is poorly tolerated Establishing RA clinics is recommended (LE, 5; DR, D; DA, 83.1%). In order to optimize therapeutic results, the panel considers especially important that patients with RA have the possibility of quick access to specialized treatment (early RA units). Response to treatment must be evaluated rigorously and periodically, with standardized procedures. Indications of biologic therapy 

The choice of biologic is an obligation of the patients’ attending physician. The biologic to be administered must be chose in function of: 1) the indication according to the insert; 2) the clinical situation and general conditions of the patient, and 3) the clinical experience of the prescribing physician. The decision should never be made with economic reasons in mind or by persons that lack clinical experience or direct responsibility in the treatment of the patient.

Evaluating response and modifications to treatment in patients  with anti-TNF

Therapeutic response to the first biologic must be evaluated at 3-4 months of starting treatment. If the objective has been reached, periodic examinations must be carried out every 3-6 months. If the objective has not been reached or the patient stops responding, the panel recommends making a new therapeutic decision (LE, 1b; DR, A; DA, 90.7%). In this sense, only three biologic agents from those currently available have shown their efficacy after failing to respond to antiTNF: ABA, RTX and TCZ, 27,28,31,35,60-62  through randomized, double blind, placebo controlled trials. Recently, Recently, data with another antianti-TNF TNF (golimumab), not yet commercialized, has been published, which also shows an efficacy similar to the abovementioned agents. 63  However, the global experience that is being collected with biologic agents and the results of other studies confirm that any therapeutic alternative used in patients with failure to a previous biologic may result effective. Among the alternatives to biologics we can find: 1. If the anti-TNF is being employed as monother monotherapy, apy, the possibility of adding MTX, with a rapid dose increase to the treatment must be evaluated before switching to another biologic. 2. If the anti-TNF is being used in combination with MTX and therapeutic response is not achieved, the following options might be considered, in no particular order of preference (DA 87.6%):  

●

 

●

 

●

 

●

Treatment after DMARD failure

Patients who have received treatment with at least one relevant DMARD and have not reached the therapeutic objective must be considered candidates for biologic therapy (LE, 1b; DR, A; DA, 95.3%). Before employing biologic therapy, a patient with RA must have received treatment with at least one DMARD, preferably MTX or LFN, in monotherapy or in combination and at an adequate dose. Only in exceptional cases should biologic therapy be considered as initial treatment (LE, 1b; DR, A; DA, 95.3%). Drugsare that, to their(ADA, insert,ETN areand indicated as first therapy theaccording three anti-TNF IFX) and TCZ, line but evidence is insufficient to recommend specific therapy therapy.. In the particular case of patients in which RA has entered remission with a specific DMARD and then presented reactivation after suspending the drug, a new DMARD treatment cycle with the drug that induced remission should be considered before considering biologic therapy. Determined comorbidities, such as chronic liver disease, infection with hepatitis C virus, can lead to the consideration of biologics before trying treatment with DMARD. Biologic therapy from the onset 

Given the evidence available that TNF a or IL-6 inhibitors induce rapid suppression of inflammation and have greater efficacy than DMARD in avoiding structural damage, the panel considers that evaluating the possibility of starting treatment with an anti-TNF (IFX, ETN, ADA) or TCZ, in combination with MTX or as monotherapy in case the first is counter c ounter-indicated, -indicated, in patients with RA of at least one year since onset and who present an especially severe progression, is  justified.15,16,19,56-59

29

If the patient is being treated with IFX, the dose may be increased or the administration interval may be shortened (LE, 4; DR, C).64  After the editorial review of this document, a clinical trial was published (LE, 2b) which did not back the dose increase of IFX from 3 to 5 mg/kg in patients who had not responded to the commonly used doses. 65  It is only one, well-performed study that uses a maximum dose below those approved. No other evidence suggesting shortening dose intervals has appeared. Switchto anotheranti-TNF, anti-TNF,independentlyof it beinga monoclonal antibody or a soluble receptor. receptor. Numerous observational studies have repeatedly shown that achieving a significant clinical response with a third anti-TNF is highly unlikely (LE, 2b; DR, B).66,67 Change the therapeutic target (RTX, ABA, TCZ) (LE, 2b; DR, B).27,35,60,62,68 If the no patient was inistreatment with TCZto as a afirst line agent, information available in order emit specific recommendation, although cumulative experience with biologics does not suggest that a different pattern than that seen with other anti-TNF anti-TNF will be observed (LE, 5; DR, D). The simultaneous administration of biologics mentioned in this document is contra-indicated (LE, 5; DR, D; DA, 88.5%). Combination of biologics in RA has shown an increase in the risk for infection without a clear clinical advantage, making their combination currently contra-indicated.

The following are acceptable options in patients who have achieved remission (LE, 5; DR, D; DA, 89.2%): ● ●

Maintain treatment with biologics. Attempt to reduce the dose, prolong the administration interva intervall or even suspend the biologic agent.

Any modification to therapy in a patient in remission requires that this clinical situation is maintained, although the timeline is yet to be defined. Reducing or suspending steroids before modifying the dose of biologics is recommended. Reducing the dose of the concomitant

 

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DMARD is not suggested before the reduction in the dose of biologic, b iologic, except in cases of DMARD toxicity. Once all treatment options with biologic agents have been explored and the therapeutic objective has not been achieved, but if both the patient and the physician observe an improvement over 20% in global disease assessment, the panel recommends that treatment with the biologic chosen for the patient should be maintained. Prior evaluation and vigilance of the patient with biologic therapy 

The fact that biologic drugs have been employed mostly in RA patients with moderate to severe disease, who by themselves have a greater risk than the general population for infections, 69 lymphomas,70  and cardiovascular disease71 must be taken into account. On the other hand, the panel considers that treatment of this disease must be undertaken by physicians who have experience with the use of biologics and are accustomed to the management of chronic inflammatory diseases of an autoimmune nature and drugs such as those exposed in this document. Whenever biologic therapy is indicated for the treatment of RA, the patient must be instructed on the appearance of red-flag symptoms that must be detected as a possible sign of drug safety issues. A strict follow-up of the course of treatment, in collaboration and communication with the primary care physician must be carried out. It is recommended that the official insert for all of the agents described in this document be reviewed and applying their recommendations before proceeding to the clinical use of the drug is recommended. Table 3 shows the evaluation that is recommended before starting treatment, as well as the vigilance that must be carried out during follow-up. Although the security profile is not exactly the same in the different options of biologic therapy, currently available information led the panel to consider that the following recommendations are applicable to all of the patients about to start biologic treatment. When a patient is about to begin with biologic therapy for RA, the possible existence of infections, cancer, heart failure, cytopenia, demyelinating disease or any other form of relevant comorbidity or contraindication for start of treatment must be taken into account (LE, 2b; DR, B; DA, 99.2%). A Spanish registry of adverse events related to biologic therapy (BIOBADASER) has found a greater incidence of infections in patients 72

strategy (surgery consisting in radical elimination of infection and, if indicated, prosthetic replacement). Very special attention must be paid to the possible development of infections during treatment. If this situation arose, an early diagnosis and treatment are fundamental, as well as the temporary suppression of biologic therapy. Faced with an increase in immigrant population and in relation to their geographical origin, it is necessary to evaluate patients for reactivations of formerly unusual infections in our country. Once the infection has been resolved, biologic therapy can be restarted. A greater incidence of tuberculosis (TB) has been seen in patients with RA who received anti-TNF, anti-TNF, especially with monoclonal antibodies.78-81  In most cases, TB appeared after 3 months of treatment, indicating a reactivation of latent TB, and presenting an infrequent pattern (extrapulmonary, (extrapulmonary, disseminated TB). The panel considers an obligation to exclude TB in all patients who are about to start biologic therapy or have had recent contact with a TB patient, as well as investigating the possibility of latent TB. Therefore it has been proposed that history of TB infection or recent contacts be documented and a chest x-ray be performed in order to rule out active TB or radiographic signs suggestive of a past infection, as well as a tuberculin test (PPD), repeated after one to two weeks if < 5 mm (LE, 2b; DR, B; DA, 100%). This test has been associated to a reduced risk of latent TB reactivation. 78,82  PPD or booster positive patients is considered if an RA patient has an induration ≥ 5 mm, after 72 h. Because it is impossible to know whether individuals who have been vaccinated with the Calmette-Guerin bacillus have a positive PPD due to the vaccion or latent TB infection, the same recommendations as those employed for non-vaccinated individuals must be followed. It is also important to instruct patients on the risks associated with the exposure to patients with active TB. Treatment for latent TB infection should be installed before the start of biologic therapy under the following circumstances: 1) recent contact with a patient with documented TB; 2) a history of partially treated TB; 3) positive PPD or booster , and 4) residual lesions seen on the chest x-ray. The choice treatment for latent TB is isoniazide (5 mg/ kg/day up to a maximum 300 mg daily) with vitamin B6 supplements, for 9 months (LE, 2b; DR, B; DA, 98.4%). In case the patient is intolerant to isoniazide, rifampin is recommended at a dose of 10 mg/kg/day (maximum, 600 mg a day) for 4 months. The effectiveness of these norms to prevent the reactivation of latent TB has been demonstrated in Spain by the important reduction seen in new cases of TB as documented by 82

with Ra receiving anti-TNF beencomorbidities: published in 17,73,74  This this regard. increase;issimilar relateddata withhas certain diabetes mellitus, high dose steroids and the concomitant use of other immunosuppresants. Infections are normally localized to the upper and lower respiratory tract, the skin and genitourinary tract. They are usually due to Staphylococcus aureus  and gram-negative germs. Likewise, a greater frequency of herpes zoster 75  has been described, and cases of opportunistic infections such as lysteria, disseminated aspergillosis and other uncommon infections in Spain, such as hystoplasmosis and coccydioidomycosis, have been reported although their incidence has been low. 76 With the rest of the biologic agents, a greater incidence of infections has also been reported. 32,61,77 An active, systemic or localized infection constitutes a contraindication for the start of biological therapy (LE, 4; DR, C; DA, 94.6%). Therefore, the use of anti-TNF agents or other biologics is not

BIOBADASER. If the patient has recently received an adequate treatment for latent or active TB, it is unnecessary to perform prophylaxis or Mantoux (LE, 5; DR, D; DA, 93.8%). However, an exhaustive exhaustive follow up is also recommended for these patients. HBV and HCV serology is recommended in candidates for biologic therapy (LE, 4; DR, C; DA, 95.3%). There have been described cases of HBV reactivation of infection in patients taking anti-TNF which have led to liver failure; many of them in patients with no prior liver anomalies. 83 With respect to HCV, it is unclear whether anti-TNF leads to deterioration of liver function or an increase in viral load, and improvement in some functional scores has even been described.84-87  However, it is recommended that an exhaustive follow up is performed in patients with RA and active HCV infection if biologics are started. In relation to the Human Immunodeficiency Virus (HIV), there are series of cases in which biologics have also been effective, but an increase in the number of

recommended in patients with a history of repeat infection or sepsis. Treatment should also not be undertaken with these drugs if there is an active, systemic or localized infection. In this sense, a history of an infected joint prosthesis forces the performance, before the start of therapy with biologics, of an adequate therapeutic

infections is also seen.88 Therefore we suggest individualizing each case and evaluating risk/benefit. The following vaccines are recommended for patients to be treated with biologics: anti-pneumococcal and the flu vaccine (LE, 3b; DR, B; DA, 95.3%).

 

 

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HBV vaccination is also recommended in patients who are to be subjected to biologic therapy (LE, 3b; DR, B; DA, 83.8%). In reference to vaccines, different publications have manifested a good humoral response in the case of anti-TNF anti-TNF for the influenza virus and pneumococcus,89-91 but data is currently contradicting in the case of RTX.92,93 In any case, these vaccines are considered poorly effective if the patient is severely immunocompromised. Once biologics are started, live vaccines should be avoided. Special attention must be paid to the development of infections during treatment. In this situation, early diagnosis and treatment, as well as temporal interruption of biologic therapy, are fundamental. Once the infection has resolved, biologic therapy can be restarted (LE, 5; DR, D; DA, 96.9%). In RA patients receiving biologics who are to be subjected to surgery, the temporary interruption of therapy is recommended (LE, 4; DR, C; DA, 91.5%). Although there is no conclusive evidence, 94-98  the panel recommends temporarily suspending biologic therapy when RA patients are to be subjected to major elective surgery, in order to reduce the risk of infection. In spite of the lack of universal agreement on the moment in which therapy is to be interrupted, it is convenient to keep the drug’s half times in mind (or the duration of the immunosuppressive effect) to decide a concrete timeline for interruption. After surgery, the panel considers that, if there are no contraindicactions or complications, biologic therapy can be reinstituted after 10-14 days. If the patient has a history of cancer, its biology and behavior must be evaluated and the possibility of a relapse must be discussed with the oncologist and the patient. If the patient contracts cancer while under treatment with a biologic, suspension is recommended (LE, 4; DR, C; DA, 90%). With respect to the appearance of tumors in patients treated with anti-TNF, there is no evidence of an increased risk of solid tumors over what is expected in an RA patients and a high degree of disease activity. 76,99,100  In any case, special attention must be given to the detection of malignant neoplasms in subjects with RA receiving biologics. Among other situations, a clinical suspicion will be established when a discrepancy is detected between the joint counts and the serum concentration of acute phase reactants, the leukocyte count or the hemoglobin concentration.101 There is discordant data on lymphoproliferative diseases,102,103  and while this question remains unclear, the use of anti-TNF a  in patients with RA and a history of lymphoproliferative disease is not recommended. Special care must be taken with anti-TNF in patients with moderato to severe heart failure because it may be aggravated (LE, 2b; DR, B; DA, 94.6%). Although current data does not always agree,104,105 patients with mild heart failure must be monitored and treatment suspended if worsening of the heart condition occurs. It is not recommended either for patients with underlying interstitial lung disease due to the risk (underdocumented) of worsening and death.106,107 Anti-TNF (and TCZ) should be suspended if a demyelinating process is suspected or optic neuritis develops, and their use is discouraged in persons with a clear history of these diseases (LE, 5; DR, D; DA, 96.9%). Anti-TNF has been related to the appearance of optic neuritis, multiple sclerosis and demyelinating processes.108,109  Faced with a case of any of these problems, treatment should be suspended and avoided if there is any history of one of these processes. Before prescribing an anti-TNF to patients in whom an increased risk of demyelinating disease has been contemplated, a careful evaluation of the risk-benefit ratio of the indication is indicated. The technical insert of TCZ recommends being on the lookout for possible demyelinating demyelinat ing effects.

33

Biologic therapy for RA treatment is not recommended if the patient has severe cytopenia. If this appears during treatment, suspension is recommended and the search for other possible causes should be undertaken before attributing it to biologic drugs (LE, 4; DR, C; DA, 87.6%). Rare cases of leucopenia, thrombocytopenia and aplastic anemia 1100 have been reported in patients treated with biologics.11 Pregnancy and lactation should be discouraged. In the case of pregnancy during treatment with biologics, suspending treatment with the biologic agent is recommended after a joint evaluation of risks and benefits (LE, 4; DR, C; DA, 90%). 1111 In general, although there is not enough evidence,11  patients with RA should be discouraged from receiving biological therapy during pregnancy or when lactating. In the case of pregnancy, biologic treatment should be suspended after evaluating with the patient the balance between risks and benefits. On the other hand, it is recommended that patients and their physicians discuss planning pregnancies in relation to the use of biologic drugs. For a more detailed analysis on aspects regarding vigilance, monitoring and recommendations related with the suspension of treatment due to security motives of each biologic drug (used as indicated, at the moment of writing this consensus, for the treatment of RA in Spain), the panel recommends reviewing Table 3.  Thank you

The panel wishes to thank the persons responsible for carrying out the systematic review, Cristina Fernández Carballido, Gloria Candelas Rodríguez, María Dolores Fabregat Canales, Francisco Gabriel Jiménez Núñez, Trinitario Pina Murcia, José Ivorra Cortés, José Rosas Gómez de Salazar, Mercedes Alperi López, José Luis Andreu Sánchez, Paloma Vela Casasempere, Enrique Casado Burgos, Ana Ortiz, Rosa González Crespo and María Piedad Rosario Lozano, SER archiver, and Loreto Carmona for her support in the consensus. Financing

The Spanish Foundation for Rheumatology funded this document. Disclosures

The following authors have received research grants of over 10,000 euros per year forJosé theLuis pastMarenco two years: Sanmartí Sala, on theperson part ofand Schering; de Raimon la Fuente, onnthe part of Wyeth; Isidoro González Álvaro, on the part of Abbott and BMS; Luis Carreño Pérez, on the part of Schering, Wyeth and Roche; Alejando Balsa Criado, on the part of Abbott, and Jesús Tornero Molina, on the part of Wyeth and Roche.

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