artritis.ppt

ARTRITIS REUMATOIDEDANNY GUSTAVOMONTENEGRO MONCAYO

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EPIDEMIOLOGAPrevalencia: 1%Relacin 3 mujeres por cada hombre.35-40 aos.

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ETIOPATOGENIA

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ETIOPATOGENIAInfiltracin LT CD4 (CD69) en sinovial (perivascular)

LTCD4 (+) Macrfagos Il1, Il6, TNF (+) LB AutoAc (FR, anticitrulina, IC)

ENFERMEDAD SISTMICA

Citoquinas PANNUS (fibroblastos, mastocitos y osteoclastos) proteasas DESTRUCCIN SEAINMUNOSUPRESORES (METOTREXATE, LEFLUNOMIDA,CTC)RITUXIMABANTI-TNF (INFLIXIMAB, ETANERCEPT)AINES, CTC

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CLNICA: ARTICULARSt generales: artromialgias, prdida de peso, febrcula, depresin...

Afectacin POLIARTICULARTumefaccin SIN ERITEMASIMTRICASt ppal: DOLOR al movimiento.Predominio articulaciones pequeas: manos y pies.RIGIDEZ matutina 1h

Las ms frecuentes: METACARPOFALNGICASMUECAINTERFALNGICAS PROXIMALES (IFP)METATARSOFALNGICAS.

Fase avanzada:Carpo en tenedorPulgar en ZDesv cubital de dedosHiperext IFP (cisne)

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CLNICA: ARTICULAR 2Otras afectaciones:Rodilla: la ms invalidante. Quiste de Baker.Columna: Subluxacin atlo-axoidea.

Rara dorsal. NO lumbar.Temporomandibular.Cricoaritenoidea: disfonaHuesecillos del odo: sordera.

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CLNICA EXTRARTICULAR. Relacionado con nivel de FRNDULOS REUMATOIDES:20-30% de los pacientes. Es un fenmeno vascultico.El 100% tienen FR +.Generalmente asintomticos. Pueden infectarse.Localizados: CODO, zonas de roce, occipucio, periarticulares, tendon de Aquiles, meninges, pleura, corazn, mdula espinalAP: centro necrtico, histiocitos en empalizada.VASCULITISPIEL: necrosis, prpura, lceras, pioderma gangrenoso.Nervioso: mononeuritis mltiple, polineuritis.Infartos viscerales.

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PLEUROPULMONAR (ms en hombres)Pleuritis con derrame pleural: Glu y ComplementoFibrosis intersticial con alteracin de la DLCOHTPulmonar (raro).Bronquiolitis obliterante en tto con penicilaminaNdulos:cavitacin, fstulas, neumotrax.Sd de CAPLAN: AR + neumoconiosisCARDACAPericarditis.Dilatacin raz A: Iao.Otras: taponamiento, arritmias

CLNICA EXTRARTICULAR

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NEUROLGICAVasculitis: mononeuritis mltiple. Vasculitis.Por compresin: Tnel carpiano, tarsiano, cervical.NO SNC.OCULAR (rara).Epiescleritis (esclera superficial roja).Escleritis: 1 CAUSA es la AR. Cuidado con escleromalacia perforante y endoftalmitis.Asociado Sd Sjogren: queratoconjuntivitis seca.OSTEOPOROSIS: asociado a CTCLINFOMA B de clulas grandes.


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SD DE FELTYESPLENOMEGALIA Tendencia a infecciones G+CITOPENIAS (neutropenia) Hiperpigmentacin de mmii y lceras.Adenopatas.Pleuropericarditis.NEFROPATAAINEs: IRe prerrenal.Sd nefrtico por amiloidosis secundaria.GMN por frmacos, per s, por vasculitisTbulo-intersticial: Sd de Sjogren.


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EROSIN MARGINALDESVIACIN DEDOS PIEFALANGES EN CUELLO DE CISNEOSTEOPENIA YUXTARTICULAR, EROSIONES

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NDULOS REUMATOIDEOSNDULOS REUMATOIDEOSSUBLUXACIN ATLO AXOIDEA

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GANGRENA DIGITALVASCULITIS LEUCOCITOCLSTICAPIODERMA GANGRENOSO

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Apoyan al dx clnico. Ningn hallazgo es dx en s.

Tumefaccin de partes blandas (lo ms precoz).Osteopenia yuxta-articular.EROSIONES SEAS:Mal pronstico si precoces.En forma de quistes subcondrales o prdida de cartlago.Luxaciones/subluxaciones.LA RX PUEDE SER NORMALLa RMN de manos ofrece mayor sensibilidad que la Rx

HALLAZGOS RADIOLGICOS

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ANALTICA GENERAL:Anemia normoctica de procesos crnicos. Leucocitosis: parmetro de inflamacin, como la trombocitosis. Con frmula N.Leucopenia en Sd de Felty (tambin trombopenia).Puede haber linfocitosis importante si se asocia a leucemia linfoide crnica T.Eosinofilia que condiciona peor pronstico.Reactantes de fase aguda: VSG, PCR, ceruloplasmina, haptoglobina, globulinas.Lquido sinovial inflamatorio: turbio, viscosidad , leucos: 2000-50000 con predominio de PMN, lactico , glucosa N o algo .

HALLAZGOS DE LABORATORIO

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FACTOR REUMATOIDE:AutoAc contra la fraccin Fc de la IgG.Sensibilidad: 75% aprox. Especificidad 70-90%.El 5% de sanos y el 15 % de ms de 65 lo tienen. (el 1/3 de los FR+ tienen AR).No sirve como screening ni como seguimiento sino como pronstico. Como diagnstico sirve para confirmar si clnica sugestiva de AR.Elevado en 100% de ndulos sc o vasculitis.Elevado en: LES, Sjogren, hepatopatas, lepra, sarcoidosis, TBC, mononucleosis, FPI, endocarditis


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AC ANTI PCC (anti pptido cclico citrulinado) o ANTICITRULINA:Sensibilidad similar al FR aunque ms precoces.Especificidad muy superior (>90%).

ANA: Aparecen a ttulos bajos en el 30%.


AC QUE NOS INTERESAN EN AR:- FACTOR REUMATOIDE- AC ANTI CITRULINA

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FACTORES DE MAL PRONSTICO:Mujeres.Edad avanzada.Afectacin rx desde el comienzo.FR, anti CCP, y reactantes de fase aguda muy elevados.Ndulos reumatoides.Persistencia del brote durante 1 ao.Nivel socioeconmico disminuido.Afectacin de ms de 20 articulaciones.MARCADORES DE ACTIVIDAD:VSG, PCR, ceruloplasmina, haptoglobina, marcadores de rotura del colgeno.

EVOLUCIN Y PRONSTICO

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La esperanza de vida se acorta de 3-7 aos (ligado a artropata ms grave) asociado a:InfeccionesHemorragia gastrointestinalEnfermedades cardiovasculares.

El tto. Precoz mitiga la clnica, secuelas y mortalidad de esta enfermedad.

EVOLUCIN Y PRONSTICO

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AR definida:- Sinovitis en una articulacin que no se explique por otros trastornos (que no sea por LES, gota Artritis psoritica).- Score >6.

A) Nmero/sitio de articulaciones comprometidas (0-5). Excepto: articulacin interfalngica distal 1ra metacarpo/metatarsofalngica.* 1 articulacin grande (hombros, codos, caderas, rodillas y tobillos) (0)* 2 - 10 grandes (1)* 1-3 articulaciones pequeas (2)* 4-10 articulaciones pequeas (3)* >10 articulaciones y que una de ellas sea pequea (5)B) Anomala serolgica (0-3)* FR (-) y pptido anti-citrulinado (-) (0)* FR dbilmente (+) PAC dbilmente (+) (2)* FR (+) y PAC (+). (3)C. RFA elevados (0-1)* PCR/VSG normales (0)* PCR alta y VSG normal (1)D. Duracin de sntomas (0-1)* 6 Semanas (1)

Fuente: ARTHRITIS & RHEUMATISM Vol. 62, No. 9, September 2010DIAGNSTICO. CRITERIOS ARA (2010)

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Drug Therapy for Rheumatoid Arthritis in Adults

Drug Therapy for Rheumatoid Arthritis in AdultsThis slide set is based on a comparative effectiveness review (CER) Drug Therapy for Rheumatoid Arthritis in Adults: An Update, which was developed by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center for the Agency for Healthcare Research and Quality under Contract No. 290-2007-10056-I and is available online at http://www.effectivehealthcare.ahrq.gov/dmardsra.cfm.

CERs are comprehensive systematic reviews of the literature that usually compare two or more types of treatment, such as different drugs or adding a second drug to usual care for the same disease. The literature included in this review was identified in searches for trials and studies that explicitly evaluated the use of drug treatments for rheumatoid arthritis in adults.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.

The goal of RA treatment is to:Control painControl inflammationLimit progressive damageReduce disease activity or induce remissionDisease-modifying anti-rheumatic drugs (DMARDs) interfere with rheumatoid disease processes by blocking the production or activity of the immune cells and their products that cause inflammation and damage.Treatment with DMARDs is increasing with the expectation that they will lead to better disease control and more remissions.Corticosteroidsboth low-dose systemic and intra-articular formulationsare used as adjuncts to DMARD treatment.Treatment of Rheumatoid ArthritisDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Treatment of Rheumatoid ArthritisThe goal of RA treatment is to control pain, control inflammation, limit progressive damage, and reduce disease activity or induce remission.

Disease-modifying anti-rheumatic drugs (DMARDs) interfere with rheumatoid disease processes by blocking the production or activity of the immune cells and their products that cause inflammation and damage. Treatment with DMARDs is increasing with the expectation that they will lead to better disease control and more remissions. Corticosteroidsboth low-dose systemic and intra-articular formulationsare used as adjuncts to DMARD treatment.


MEDIDAS GENERALESAINES: sintomticos que no modifican la progresin.CTC: sintomticos que s modifican el curso.FAME (modificadores) sintticos:Metotrexate, leflunomidaAntiguos: sulfasalacina, antipaldicos.No se utilizan : sales de oro, d-penicilamina.Otros inmunosupresores de 2 lnea: ciclosporina, azatioprina, ciclofosfamida.FAME biolgicos:AntiTNF: Infliximab, adalimumab, etanercept.Anti Il1: anakinra.AntiCD20: rituximabAnti CTLA4: abatacept.

TRATAMIENTO

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MEDIDAS GENERALES:Informacin continua de la enfermedad y tto.Modificaciones oportunas del entorno.Mayor reposo en fases de mayor actividad.Ejercicio para mantener fuerza muscular y movilidad de las articulaciones.Dieta con cidos poliinsaturados (omega 3).

TRATAMIENTO

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En 1 lnea de tratamiento, considerndolo ms bien como alivio sintomtico:

AINEs:(-) COOX1: Eficaces antiinflamatorios. Morbilidad digestiva. Cardioproteccin.(-) COOX2: -coxib: Igual eficacia. Menos morbilidad digestiva. No cardioproteccin.Hay que aadir IBP y como tambin tienen toxicidad renal y + HTA hay que ponerlos a bajas dosis y quitarlos si se puede.

CORTICOIDES:S modifican el curso aunque poco. Terapia puente.Prednisona o prednisolona a baja dosis.

TRATAMIENTO

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Comenzar desde el principio si signos de actividad de la enfermedad.Asociar FAME (MTX+anti TNF) es lo que mejor resultado da ahora.METOTREXATOEl FAME de eleccin INICIAL. Puede utilizarse como monoterapia.Problemas: mucositis orointestinal, hepatopata, anemia (prevenir administrando ac folnico).LEFLUNOMIDA:Inmunosupresor anti LT.De segunda lnea tras MTX.Problemas: hepatopata.

TRATAMIENTO. FAMEOTROS INMUSUPRESORES:-CICLOSPORINA-AZATIOPRINA-CICLOFOSFAMIDA

Si enfermedad sistmica

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TERAPIAS BIOLGICAS (ANTICITOCINAS):Se utilizan si las terapias con MTX asociado a otros FAME no han ido bien (esto dicen las guas aunque ya se utiliza como primera lnea junto a MTX). Se asocian a los anteriores.Predisponen a infecciones, especialmente reactivacin de TBC: HACER MANTOUX.Incrementan el riego de neoplasias: linfoma.ANTITNF: INFLIXIMAB, ADALIMUMAB, ETANERCEPT, GOLIMUMAB, CERTOLIZUMABANTI IL1: ANAKINRAANTI CD20(antiLB): RITUXIMABANTI CTLA4 (LT): ABATACEPTANTI IL-6: TOCILIZUMAB

TRATAMIENTO. FAME

Si fallan los ANTI TNF

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CONVENCIONALES DE ACCIN LENTA:Slo se siguen utilizando la hidroxicloroquina y la sulfasalazina.Cada vez se utilizan menos habiendo sido desplazados por los FAME.

TRATAMIENTO. FAME

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GUA DE TRATAMIENTOSI AFECTACIN SISTMICA: CICLOFOSFAMIDA, AZATIOPRINA, CICLOSPORINA.

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Disease-modifying anti-rheumatic drugs (DMARDs) are in common use for rheumatoid arthritis (RA), and several have been approved by the U.S. Food and Drug Administration for this indication.DMARDs may be oral or biologic drugs.The consensus of clinical experience has made methotrexate, an oral DMARD, the first-line drug of choice for treating RA.

DMARDs in Rheumatoid Arthritis Treatment (1 of 2)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

DMARDs in Rheumatoid Arthritis Treatment (1 of 2)Disease-modifying anti-rheumatic drugs (DMARDs) are in common use for rheumatoid arthritis (RA), and several have been approved by the U.S. Food and Drug Administration for this indication. DMARDs may be oral or biologic drugs.

The consensus of clinical experience has made methotrexate, a oral DMARD, the first-line drug of choice for treating RA.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.

Oral disease-modifying anti-rheumatic drugs (DMARDs) are small-molecule chemical drugs.The mechanism of action of each of these drugs is not well defined and is unknown in some cases.Biologic DMARDs block the activity of immunostimulatory cytokines and other cell-signaling molecules.Biologic DMARDs are genetically engineered antibodies and proteins.Tumor necrosis factor-alpha blockers are the most typical members of this drug class.Other targets are interleukins 1 and 6 and the transmembrane proteins CD20 and CD28.DMARDs in Rheumatoid Arthritis Treatment (2 of 2)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

DMARDs in Rheumatoid Arthritis Treatment (2 of 2)Oral disease-modifying anti-rheumatic drugs (DMARDs) are small-molecule chemical drugs. The mechanism of action of each of these drugs is not well defined and is unknown in some cases.

Biologic DMARDs block the activity of immunostimulatory cytokines and other cell-signaling molecules. They include genetically engineered antibodies and proteins. Tumor necrosis factor-alpha blockers are the most typical members of this drug class. Other targets are interleukins 1 and 6 and the transmembrane proteins CD20 and CD28.


Oral DMARDs Included in the Comparative Effectiveness ReviewDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Oral Disease-Modifying anti-rheumatic DrugsNameTarget of ActivityHydroxychloroquineT-lymphocytes (?)LeflunomidePyridine synthesisMethotrexateDihydrofolate reductase; folate metabolism SulfasalazineUncertain; multifactorial, including impairment of lymphocyte function and cytokine synthesis

Oral DMARDs Included in the Comparative Effectiveness ReviewThe oral disease-modifying anti-rheumatic drugs that have been studied for treatment of rheumatoid arthritis and were included in the comparative effectiveness review are:

Hydroxychloroquine: Its target of activity is uncertain but likely is T-lymphocytes.Leflunomide: Its target of activity is pyridine synthesis.Methotrexate: Its target of activity is dihydrofolate reductase and folate metabolism.Sulfasalazine: Its target of activity is uncertain but may be multifactorial, including impairment of lymphocyte function and cytokine synthesis.


Biologic DMARDs Included in the Comparative Effectiveness ReviewDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.Abbreviations: IL = interleukin; TNF- = tumor necrosis factor-alpha

Biologic Disease-Modifying anti-rheumatic DrugsNameTrade NameTarget of ActivityAdalimumabHumiraTNF-Certolizumab pegolCimziaTNF-EtanerceptEnbrelTNF-GolimumabSimponiTNF-InfliximabRemicadeTNF-AbataceptOrenciaCD28AnakinraKineretIL-1RituximabRituxanCD20TocilizumabActemraRoActemraIL-6 receptor

Biologic DMARDs Included in the Comparative Effectiveness ReviewThe biologic disease-modifying anti-rheumatic drugs (DMARDs) that have been studied for treatment of rheumatoid arthritis and were included in the comparative effectiveness review are:

The biologic DMARDs that target tumor necrosis factor-alpha (TNF-) include adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade).

Other biologic DMARDs included in the review target immune system components other than TNF-. They are:

Abatacept (Orencia): Its target of activity is CD28.Anakinra (Kineret): Its target of activity is interleukin 1.Rituximab (Rituxan): Its target of activity is CD20.Tocilizumab (Actemra, RoActemra): Its target of activity is the interleukin-6 receptor.


The strength of evidence was classified into four broad categories:Rating the Strength of Evidence From the Comparative Effectiveness ReviewAgency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at www.effectivehealthcare.ahrq.gov/methodsguide.cfm.

Rating the Strength of Evidence From the Comparative Effectiveness ReviewThe Evidence-based Practice Center GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as high (further research is very unlikely to change the confidence in the estimate of effect), moderate (further research may change the confidence in the estimate of effect and may change the estimate), low (further research is likely to change the confidence in the estimate of effect and is likely to change the estimate), or insufficient (evidence either is unavailable or does not permit a conclusion). The authors also independently evaluated the applicability to real-world practice of the total body of evidence within a given clinical indication by using the PICOTS (population, intervention, comparator, outcome, timing, and setting) framework.

References:Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 10(12)-EHC063-EF. Chapters available at www.effectivehealthcare.ahrq.gov/methodsguide.cfm.

Brozek J, Oxman A, Schnemann H, for the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADEpro [computer program]. Version 3.2 for Windows. Available at www.ims.cochrane.org/revman/other-resources/gradepro/gradepro.

In analyzing the clinical study evidence, reviewers focused on these outcomes of benefit:Disease activity and symptomsACR 20/50/70: American College of Rheumatology response scoresDAS and DAS28: disease activity scoreRadiographic changesSharp/van der Heijde Method (SHS) for scoring radiographsFunctional capacityHAQ: Health Assessment QuestionnaireHAQ-DI: disability index of the Health Assessment QuestionnaireQuality of lifeSF-36EQ-5DClinically Significant Outcomes of Interest in the Comparative Effectiveness ReviewDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Clinically Significant Outcomes of Interest in the Comparative Effectiveness ReviewIn analyzing the clinical study evidence, reviewers focused on these outcomes of benefit and corresponding assessment instruments or scoring indices:

- Disease activity and symptoms were evaluated using American College of Rheumatology response scores (ACR 20/50/70) and DAS and DAS28 disease activity scores.- Radiographic changes were measured using the Sharp/van der Heijde Method (SHS) for scoring radiographs.- Functional capacity was evaluated by the Health Assessment Questionnaire (HAQ) and the disability index of HAQ (HAQ-DI).- Quality of life was measured using the SF-36 and EQ-5D questionnaires.


Leflunomide and methotrexate (MTX; 7.5 to 25 mg/week) have similar effects on symptom response, radiographic change, and functional capacity.Strength of Evidence = LowLeflunomide may be superior to sulfasalazine for improving functional capacity. Strength of Evidence = LowSulfasalazine and MTX (7.5 to 25 mg/week) have similar effects on symptoms, disease activity, functional capacity, and limiting radiographic changes (in patients with rheumatoid arthritis for

In patients with longstanding active rheumatoid arthritis (RA), combining up to three oral disease-modifying anti-rheumatic drugs (DMARDs; methotrexate [MTX], sulfasalazine, and hydroxychloroquine) produces greater improvements in disease activity than one or two oral DMARDs. Strength of Evidence = ModerateFor patients with early RA who have not previously been treated with oral DMARDs, combining oral DMARDs (sulfasalazine and MTX) does not improve symptom response, radiographic progression, or functional capacity more than monotherapy. Strength of Evidence = ModerateSummary of Benefits:Combination Treatments With Oral DMARDsDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Summary of Benefits: Combination Treatments With Oral DMARDsThe comparative benefits of combination treatments with oral disease-modifying anti-rheumatic drugs (DMARDs) may be summarized as follows:

- In patients with longstanding active rheumatoid arthritis (RA), combining up to three oral DMARDs (methotrexate [MTX], sulfasalazine, and hydroxychloroquine) produces greater improvements in disease activity than one or two oral DMARDs. The strength of evidence for this finding is moderate.- For patients with early RA who have not previously been treated with oral DMARDs, combining oral DMARDs (sulfasalazine and MTX) does not improve symptom response, radiographic progression, or functional capacity more than monotherapy. The strength of evidence for this finding is moderate.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm

Summary of Results: Head-to-Head Comparisons of Biologic DMARDsIn patients with active RA (>3 years), with failed or inadequate disease response to DMARDs who did not receive an antiTNF- DMARD, head-to-head comparisons of DMARDs produced the following results:Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

InterventionComparatorSymptoms or Disease Activity* (N Studies; N Patients)Function(N Studies; N Patients)Quality of Life(N Studies; N Patients)EtanerceptInfliximabFaster response with etanercept, but NSD in the longer term(6; 5,883) SOE = Low2 of 3 studies reported NSD(3; 2,239) InsufficientInsufficientEtanerceptAdalimumabACR70 at 6 months showed NSD (1; 2,326) SOE = LowNSD(1; 707) SOE = LowNSD(1; 707) SOE = LowAdalimumabInfliximabSymptom response (ACR20 at 6 months) and DAS at 1 year greater with adalimumab(2; 3,033) SOE = LowGreater improvement at 12 months with adalimumab but not greater than the MCID(1; 707) SOE = LowSF-36 physical component at 12 months favors adalimumab(1; 707) SOE = InsufficientAbataceptInfliximabGreater decrease in DAS and greater remission rate, both at 1 year, with abatacept. (3; 3,464) SOE = LowNSD at 1 year(1; 431) SOE = LowSF-36 physical component at 1 year favors abatacept but not greater than the MCID (1; 431) SOE = Low*Radiographic progression not reported.

Summary of Results: Head-to-Head Comparisons of Biologic DMARDsHead-to-head comparisons of biologic DMARDs were evaluated for the effectiveness review. Patient populations in the included studies were patients with active RA for longer than 3 years whose disease not did respond or inadequately responded to DMARDs but had not previously treated with an antiTNF- DMARD. This table presents a summary of the results of those studies, organized according to the interventions compared in each study. Disease activity and symptom response, functional status, and quality-of-life outcomes were reported. Radiographic evidence of progression was not reported in the studies. The evidence is limited for all comparisons; thus, the strength of evidence is low or insufficient.

Abbreviations:ACR70 = American College of Rheumatology 70-percent improvement criteria; ACR20 = American College of Rheumatology 20-percent improvement criteria; DAS = Disease Activity Score; DMARD = disease-modifying anti-rheumatic drug; MCID = minimum clinically important difference; NSD = no statistically significant difference; RA = rheumatoid arthritis; SOE = strength of evidence; TNF- = tumor necrosis factor-alpha


Comparisons of Biologic DMARDs Across Controlled Studies: Mixed Treatment ComparisonsThe authors of the comparative effectiveness review used data from placebo-controlled trials to compare biologic DMARDs across studies, using an analytic method called mixed treatment comparison. The patient populations in the studies had MTX-resistant rheumatoid arthritis. The outcome analyzed was the rate of achieving an ACR50 response to treatment.The studies included the biologic DMARDs abatacept, adalimumab, anakinra, etanercept, golimumab, infliximab, rituximab, and tocilizumab.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.Abbreviations: ACR50 = American College of Rheumatology 50-percent response criteria; DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; SOE = strength of evidence

InterventionComparatorPatient CharacteristicsReduced Symptoms or Disease Activity Biologic DMARDsBiologic DMARDsPatients whose rheumatoid arthritis is resistant to MTXEtanercept yields the greatest ACR50 response when compared with other biologic DMARDs, and anakinra yields the lowestSOE = Low30 placebo-controlled trials6,888 patients

Comparisons of Biologic DMARDs Across Controlled Studies: Mixed Treatment ComparisonsThe authors of the comparative effectiveness review used data from placebo-controlled trials to compare biologic disease-modifying anti-rheumatic drugs (DMARDs) across studies, using an analytic method called a mixed treatment comparison. The patient populations in the studies had methotrexate-resistant rheumatoid arthritis. The outcome analyzed was the rate of achieving the American College of Rheumatology 50-percent response criteria (ACR50). Thirty placebo controlled trials with a total of 6,888 patients included the biologic DMARDs abatacept, adalimumab, anakinra, etanercept, golimumab, infliximab, rituximab, and tocilizumab. The analysis demonstrated that etanercept yields the greatest ACR50 response when compared with other biologics and that anakinra yields the lowest. However, the strength of evidence is low, as the comparisons are indirect.


Summary of Results: Comparative Benefits of Biologic DMARDs Used in CombinationDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

InterventionComparatorPatient CharacteristicsSymptoms or Disease Activity* FunctionQuality of LifeBiologic DMARD CombinationsBiologic DMARDMonotherapyPatients with longstanding, active RADisease activity NSD(2; 363)SOE = LowNo Clinically Significant Difference (1; 121)SOE = LowCombinations improve physical but not mental quality of life (1; 121)SOE = Low*Radiographic progression was not reported.DMARD = disease-modifying anti-rheumatic drug; NSD = no statistically significant difference; RA = rheumatoid arthritis; SOE = strength of evidence

Summary of Results: Comparative Benefits of Biologic DMARDs Used in CombinationTwo randomized controlled trials examined the benefits of combining two biologic DMARDs when compared with biologic DMARD monotherapy. The patient populations were those patients with longstanding active rheumatoid arthritis, rather than those with early disease. No statistically significant differences were noted in disease activity, function, or quality-of-life indices.


Summary of Results: Head-to-Head Comparisons of Oral and Biologic DMARDsDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Intervention(N Studies,N Patients)ComparatorSymptoms or Disease Activity Radiographic Evidence of ProgressionFunctional CapacityIn patients with longstanding active RA who required a change in therapy*:Biologic DMARDs as a classOral DMARDs as a classHigher chance of remission with biologics than with oral DMARDsSOE = ModerateNRInsufficient1 retrospective cohort studyN = 1,083Biologic DMARDsOral DMARDsHigher response rates for biologic DMARDs SOE = ModerateNRInsufficient4 RCTs, 2 cohort studiesN = 3,696* Health-related quality of life was not reported.DMARD = disease-modifying anti-rheumatic drug; NR = not reported; RA = rheumatoid arthritis; RCT = randomized controlled trial; SOE = strength of evidence

Summary of Results: Head-to-Head Comparisons of Oral and Biologic DMARDsThe reviewed studies included direct comparisons of oral and biologic disease-modifying anti-rheumatic drugs (DMARDs) used to treat patients with longstanding active rheumatoid arthritis who required a change in therapy. A retrospective cohort study of 1,083 patients found that as a class, biologic DMARDs resulted in more remissions when compared with oral DMARDs as a class. The systematic review found that biologic DMARDs achieved a higher response rate than oral DMARDs. The strength of evidence for this finding is moderate.

Four randomized controlled trials and two retrospective cohort studies evaluated 3,696 patients in comparisons of biologic DMARDs with oral DMARDs. Higher symptom response rates were found with biologic DMARDs. The strength of the evidence for this conclusion is moderate.

Radiographic evidence of progression was not reported in the studies presented here, and evidence for findings of effect on functional capacity was insufficient to permit conclusions.


Considered as a class, for patients with longstanding active rheumatoid arthritis requiring a change in therapy, biologic disease-modifying anti-rheumatic drugs (DMARDs) provide a greater symptom response and remission rate than do the oral DMARDs. Strength of Evidence = ModerateOverall, the evidence about functional capacity and quality of life is insufficient to permit estimates of comparative effectiveness. Strength of Evidence = InsufficientCombining two biologic DMARDs (etanercept with abatacept or anakinra) does not add to improvement in disease activity, functional capacity, or symptom response more than one biologic DMARD and increases the risk of serious adverse effects. Strength of Evidence = LowComparisons across studies of patients whose disease is resistant to suggest that there may be clinically observable differences in the efficacy of the biologic DMARDs. Evidence from head-to-head comparisons is too limited to provide guidance for clinical decisionmaking. Strength of Evidence = LowSummary of Benefits: Biologic DMARDsDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Summary of Benefits: Biologic DMARDsConsidered as a class, for patients with longstanding active rheumatoid arthritis requiring a change in therapy, biologic disease-modifying anti-rheumatic drugs (DMARDs) provide greater symptom response and remission rate than do the oral DMARDs. The strength of evidence for this conclusion is moderate.Overall, the evidence about functional capacity and quality of life is insufficient to permit estimates of comparative effectiveness.

Considered as a class, for patients with longstanding active disease requiring a change in therapy, biologic DMARDs provide greater symptom response and remission rate than do the oral DMARDs.

Combining two biologic DMARDs (etanercept with abatacept or anakinra) does not add to improvement in disease activity, functional capacity, or symptom response more than one biologic DMARD and increases the risk of serious adverse effects. The strength of evidence for this conclusion is low.

Comparisons across studies of patients whose disease is resistant to methotrexate suggest that there may be clinically observable differences in the efficacy of the biologic DMARDs. Evidence from head-to-head comparisons is too limited to provide guidance for clinical decisionmaking. The strength of evidence for this conclusion is low.


Summary of Results: DMARD Combinations Versus MonotherapiesIn patients with longstanding active rheumatoid arthritis with inadequate disease control, head-to-head comparisons of combined DMARDs and DMARD monotherapy were conducted.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Intervention*ComparatorSymptoms or Disease Activity(N Studies; N Participants) Radiographic Progression(N Studies;N Participants) Function(N Studies; N Participants) Quality of Life(N Studies; N Participants) Biologic DMARD plus MTXBiologic DMARDMonotherapy(5 RCT, 4 cohort; 9,804)Combination is more effectiveSOE = Moderate(2; 1, 495)Less change with a combinationSOE = Moderate(2; 1,495)Combination treatment is more effectiveSOE = Moderate(2; 1,495)Combination treatment is more effective.SOE = LowBiologic DMARD plus MTX or SSZMTX or SSZMonotherapy(7; 4,482)Combination is more effectiveSOE = High(7; 4,482)Less change with combinationSOE = Moderate(7 RCT, 1 cohort; 7,516)Combination treatment is more effectiveSOE = High(7 RCT, 1 cohort; 7, 516)Combination treatment is more effectiveSOE = Moderate* Patients with active disease whose disease did not respond to an oral DMARD did not benefit from including that oral DMARD in combination with a biologic DMARD. MTX was used at a dose of 7.5 to 25mg per week in the reported studies.

Summary of Results: DMARD Combinations Versus MonotherapiesIn patients with longstanding active rheumatoid arthritis with inadequate disease control, head-to-head comparisons were made of combined DMARDs and DMARD monotherapy. Overall, combination treatment with biologic DMARDs and an oral DMARD is more effective than either used as monotherapy. Disease activity, radiographic progression, functional status, and quality of life all are greater improved with the combination therapy. The strength of evidence for these findings varies among the specific outcomes, with most supported by moderate or high strength of evidence.

Abbreviations:DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; RA = rheumatoid arthritis; RCT = randomized controlled trial; SOE = strength of evidence; SSZ = sulfasalazine


Summary of Results: DMARD Combinations Versus MonotherapiesIn patients with early rheumatoid arthritis who had not been treated with methotrexate (MTX), or who had not received MTX in the previous 3 months, headtohead comparisons of combination therapy and MTX monotherapy were examined for effects on function and quality of life.Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

InterventionComparatorPatient CharacteristicsFunction(N Studies; N Participants) Quality of Life(N Studies; N Participants) Biologic DMARD plus MTX*MTX* monotherapyEarly RA MTX Nave or not recently on MTX*(2; 1,495)Combination is more effective.SOE = Moderate(2; 1,495)Combination is more effective.SOE = Low* Methotrexate was used at 7.5 to 25mg per week in the reported studies. Early RA is defined as disease of as less than 3 years duration.DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; RA = rheumatoid arthritis; SOE = strength of evidence

Summary of Results: DMARD Combinations Versus MonotherapiesIn patients with early rheumatoid arthritis who had not been treated with methotrexate (MTX), or who had not received MTX in the previous 3 months, headtohead comparisons of combination therapy and MTX monotherapy were examined for effects on function and quality of life. Combination therapy was more effective in achieving improvements in function and quality of life. The strength of evidence is moderate for functional status and low for quality of life.


In patients with rheumatoid arthritis who had inadequate disease control and required a change in treatment, combination therapy with a biologic disease-modifying anti-rheumatic drug (DMARD) and methotrexate (MTX) achieved greater improvements in some outcomes than either a biologic DMARD or MTX alone.Combination therapy achieves greater improvement than biologics alone in:Disease activity and radiographic progression Strength of Evidence = ModerateCombination therapy achieves greater improvement than MTX alone in:Clinical response and functional capacity Strength of Evidence = HighQuality of lifeStrength of Evidence = ModerateSummary of Benefits: DMARD Combinations Versus Monotherapies (1 of 2)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Summary of Benefits: DMARD Combinations Versus Monotherapies (1 of 2)In patients with rheumatoid arthritis who had inadequate disease control and required a change in treatment, combination therapy with a biologic disease-modifying anti-rheumatic drug (DMARD) and methotrexate (MTX) achieved greater improvements in some outcomes than either a biologic DMARD or MTX alone.

Combination therapy achieves greater improvement than biologics alone in disease activity and radiographic progression (Strength of Evidence = Moderate).

Combination therapy achieves greater improvement than MTX alone in clinical response and functional capacity (Strength of Evidence = High) as well as in quality of life (Strength of Evidence = Moderate).


In patients whose rheumatoid arthritis failed to respond to methotrexate (MTX), combination therapy with MTX and a biologic disease-modifying anti-rheumatic drug (DMARD) was not more successful than monotherapy with a biologic DMARD. Strength of Evidence = ModerateIn MTX-nave patients or those had not taken MTX recently, combination therapy is superior to monotherapy with a biologic DMARD for functional capacity and quality of life. Strength of Evidence for Functional Capacity = ModerateStrength of Evidence for Quality of Life = LowSummary of Benefits: DMARD Combinations Versus Monotherapies (2 of 2)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Summary of Benefits: DMARD Combinations Versus Monotherapies (2 of 2)In patients whose rheumatoid arthritis failed to respond to methotrexate (MTX), combination therapy with MTX and a biologic disease-modifying anti-rheumatic drug (DMARD) was not more successful than monotherapy with a biologic DMARD. The strength of evidence for this finding is moderate.

In MTX-nave patients or those not taken MTX recently, combination therapy is superior to monotherapy with a biologic DMARD for functional capacity and quality of life. The strength of evidence for functional capacity is moderate and for quality of life is low.


Summary of Results: Comparative Benefits of Oral and Biologic DMARDs for Patients With Early RADonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Patient CharacteristicsInterventionComparatorReduced Symptoms or Disease Activity Limiting Radiographic ProgressionImproved FunctionPatients with early RA*2 to 3 oral DMARDs plus corticosteroidsOral DMARDMonotherapyCombination is more effective at 28 but not 52 weeks.(2; 354) SOE = LowCombination is more effective(2; 354)SOE = LowCombination is more effective (2; 354)SOE = LowMTX-nave patients with aggressive early RAMTXAdalimumab, EtanerceptResults are similar(2; 1,431)SOE = ModerateBiologic DMARD is more effective at limiting progression.(2; 1,431)SOE = LowResults are similar with MTX and adalimumab(2; 1,431)SOE = Low

MTX-nave patients with aggressive early RAMTX plus biologic DMARDBiologic DMARD MonotherapyCombination is more effective(also improves remission rates)(1; 799) SOE = LowCombination is more effective.(1; 799) SOE = LowNR* Early RA is disease of less than 3 years duration. Combination treatment is also more effective at improving quality of life. Methotrexate was used at a dose of 7.5 to 25mg per week in the reported studies. Quality-of-life outcomes were not reported.

Summary of Results: Comparative Benefits of DMARDs for Patients With Early RASome clinical research has focused on treatment of patients with early rheumatoid arthritis, defined for this comparative effectiveness review as less than 3 years duration of disease. This table presents a summary of the results of those studies, organized according to the patient characteristics and by the interventions compared in the study. Disease activity and symptom response, radiographic evidence of progression, and functional status were reported. Quality-of-life outcomes were not reported in the studies. The strength of evidence is moderate for one conclusion, finding that methotrexate and adalimumab or etanercept produce similar effects on symptoms. The evidence is limited for all other comparisons, making the strength of evidence low.

Abbreviations:DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; NR = not reported; RA = rheumatoid arthritis; SOE = strength of evidence


Combination strategies that use corticosteroids plus two or three oral disease-modifying anti-rheumatic drugs (DMARDs) are more effective than oral DMARD monotherapy for improving symptom response, disease activity, and functional capacity in patients with rheumatoid arthritis (RA) in the short term and reducing radiographic evidence of progression and joint erosion in the longer term (1 year). Combining one oral DMARD with prednisone reduces radiographic progression and joint erosion more than the DMARD alone. For patients with early RA who have not been treated with methotrexate (MTX):Effects on symptom response are similar when MTX is compared with adalimumab or etanercept. Effects on functional capacity are similar with MTX and adalimumab. Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (1 of 2)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (1 of 2)Combination strategies that use corticosteroids plus two or three oral DMARDs are more effective than oral DMARD monotherapy for improving symptom response, disease activity, and functional capacity in patients with rheumatoid arthritis in the short term and reducing radiographic evidence of progression and joint erosion in the longer term (1 year).

Combining one oral DMARD with prednisone reduces radiographic progression and joint erosion more than the DMARD alone.

For patients with early RA who have not been treated with methotrexate (MTX):- Effects on symptom response are similar when MTX is compared with adalimumab or etanercept.- Effects on functional capacity are similar with MTX and adalimumab.


Biologic disease-modifying anti-rheumatic drugs (DMARDs) more effectively limit radiographic evidence of progression than do oral DMARDs. For methotrexate (MTX)-nave patients with aggressive early rheumatoid arthritis, combining MTX with a biologic DMARD (abatacept, adalimumab, etanercept, or infliximab) provides greater improvement than biologic DMARD monotherapy for symptom response, clinical remission rates, and radiographic progression. Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (2 of 2)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Summary of Benefits: DMARDs in the Treatment of Patients With Early Rheumatoid Arthritis (2 of 2)Biologic disease-modifying anti-rheumatic drugs (DMARDs) more effectively limit radiographic evidence of progression than do oral DMARDs.

For methotrexate (MTX)-nave patients with aggressive early rheumatoid arthritis, combining MTX with a biologic DMARD (abatacept, adalimumab, etanercept, or infliximab) provides greater improvement than biologic DMARD monotherapy for symptom response, clinical remission rates, and radiographic progression.


For patients with early rheumatoid arthritis (RA)who have not been treated with methotrexate (MTX), treatment with either MTX or a biologic disease-modifying anti-rheumatic drug (DMARD) provides similar benefits for symptoms and function. However, biologic DMARDs are more effective at limiting radiographic evidence of progression. The evidence is too limited to permit conclusions about whether one combination strategy is better than another in treating early RA (

Indirect comparisons reveal potential differences in effectiveness of the biologic disease-modifying anti-rheumatic drugs (DMARDs) in treating rheumatoid arthritis, but the analysis should be interpreted with caution.Combining biologic DMARDs provides no additional benefits and increases the risk of serious adverse effects. In patients with inadequate disease control, biologic DMARDs used in combination with methotrexate (MTX) offer greater relief than monotherapy with either MTX of a biologic DMARD without increasing treatment discontinuation due to adverse effects.Conclusions (2 of 4)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Conclusions (2 of 4)Indirect comparisons reveal potential differences in effectiveness of the biologic disease-modifying anti-rheumatic drugs (DMARDs) in treating rheumatoid arthritis, but the analysis should be interpreted with caution.

Combining biologic DMARDs provides no additional benefits and increases the risk of serious adverse effects.

In patients with inadequate disease control, biologic DMARDs used in combination with methotrexate (MTX) offer greater relief than monotherapy with either MTX or a biologic DMARD without increasing treatment discontinuation due to adverse effects.


The oral disease-modifying anti-rheumatic drugs (DMARDS), particularly methotrexate (MTX), remain effective first-line treatments for rheumatoid arthritis (RA).MTX (at a dose of 7.5 to 25 mg per week) and sulfasalazine are similarly effective for patients with early RA, and leflunomide may provide comparable results. Adding prednisone to treatment with oral DMARDs improves function and may limit radiographic progression, although there is evidence that the combination increases the risks of adverse effects. For patients with longstanding active disease, two or three oral DMARDs in combination can provide more improvement than monotherapy.Conclusions (3 of 4)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Conclusions (3 of 4)The oral disease-modifying anti-rheumatic drugs (DMARDS), particularly methotrexate (MTX), remain effective first-line treatments for rheumatoid arthritis (RA).

MTX (at a dose of 7.5 to 25 mg per week) and sulfasalazine are similarly effective for patients with early RA, and leflunomide may provide comparable results.

Adding prednisone to treatment with oral DMARDs improves function and may limit radiographic progression, although there is evidence that the combination increases the risks of adverse effects.

For patients with longstanding active disease, two or three oral DMARDs in combination can provide more improvement than monotherapy.


Disease-modifying anti-rheumatic drugs (DMARDs) of both classes are associated with well-known adverse effects (toxicity of oral DMARDs, serious infections with biologic DMARDs), but the comparative risks are not known. Overall tolerability is similar between DMARDs of both classes. The evidence about cancer risk is limited, but the risk for patients with rheumatoid arthritis does not appear to be elevated by DMARDs of either class.Conclusions (4 of 4)Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

Conclusions (4 of 4)Disease-modifying anti-rheumatic drugs (DMARDs) of both classes are associated with well-known adverse effects (toxicity of oral DMARDs, serious infections with biologic DMARDs), but the comparative risks are not known.

Overall tolerability is similar between DMARDs of both classes. The evidence about cancer risk is limited, but the risk for patients with rheumatoid arthritis does not appear to be elevated by DMARDs of either class.


The natural history of rheumatoid arthritis (RA) and the role of disease-modifying anti-rheumatic drugs (DMARDs) in reducing symptoms and improving disease controlThe potential benefits and adverse effects of DMARDsChanges in lifestyle that can help relieve RA symptoms, such as diet and exercisePatient and caregiver preferences and values regarding treatmentWhat To Discuss With Your Patients and Their CaregiversDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

What To Discuss With Your Patients and Their CaregiversIn discussions with patients who have rheumatoid arthritis (RA) and their caregivers, topics related to the comparative effectiveness review evidence include the natural history of RA, the role of disease-modifying anti-rheumatic drugs (DMARDs) in reducing symptoms and improving disease control, the potential benefits and adverse effects of DMARDs, changes in lifestyle that can help relieve symptoms (e.g., diet and exercise), and patient and caregiver preferences and values regarding treatment.


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*Drug Therapy for Rheumatoid Arthritis in AdultsThis slide set is based on a comparative effectiveness review (CER) Drug Therapy for Rheumatoid Arthritis in Adults: An Update, which was developed by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center for the Agency for Healthcare Research and Quality under Contract No. 290-2007-10056-I and is available online at http://www.effectivehealthcare.ahrq.gov/dmardsra.cfm.

CERs are comprehensive systematic reviews of the literature that usually compare two or more types of treatment, such as different drugs or adding a second drug to usual care for the same disease. The literature included in this review was identified in searches for trials and studies that explicitly evaluated the use of drug treatments for rheumatoid arthritis in adults.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.Treatment of Rheumatoid ArthritisThe goal of RA treatment is to control pain, control inflammation, limit progressive damage, and reduce disease activity or induce remission.

Disease-modifying anti-rheumatic drugs (DMARDs) interfere with rheumatoid disease processes by blocking the production or activity of the immune cells and their products that cause inflammation and damage. Treatment with DMARDs is increasing with the expectation that they will lead to better disease control and more remissions. Corticosteroidsboth low-dose systemic and intra-articular formulationsare used as adjuncts to DMARD treatment.


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*DMARDs in Rheumatoid Arthritis Treatment (1 of 2)Disease-modifying anti-rheumatic drugs (DMARDs) are in common use for rheumatoid arthritis (RA), and several have been approved by the U.S. Food and Drug Administration for this indication. DMARDs may be oral or biologic drugs.

The consensus of clinical experience has made methotrexate, a oral DMARD, the first-line drug of choice for treating RA.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.DMARDs in Rheumatoid Arthritis Treatment (2 of 2)Oral disease-modifying anti-rheumatic drugs (DMARDs) are small-molecule chemical drugs. The mechanism of action of each of these drugs is not well defined and is unknown in some cases.

Biologic DMARDs block the activity of immunostimulatory cytokines and other cell-signaling molecules. They include genetically engineered antibodies and proteins. Tumor necrosis factor-alpha blockers are the most typical members of this drug class. Other targets are interleukins 1 and 6 and the transmembrane proteins CD20 and CD28.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.Oral DMARDs Included in the Comparative Effectiveness ReviewThe oral disease-modifying anti-rheumatic drugs that have been studied for treatment of rheumatoid arthritis and were included in the comparative effectiveness review are:

Hydroxychloroquine: Its target of activity is uncertain but likely is T-lymphocytes.Leflunomide: Its target of activity is pyridine synthesis.Methotrexate: Its target of activity is dihydrofolate reductase and folate metabolism.Sulfasalazine: Its target of activity is uncertain but may be multifactorial, including impairment of lymphocyte function and cytokine synthesis.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.Biologic DMARDs Included in the Comparative Effectiveness ReviewThe biologic disease-modifying anti-rheumatic drugs (DMARDs) that have been studied for treatment of rheumatoid arthritis and were included in the comparative effectiveness review are:

The biologic DMARDs that target tumor necrosis factor-alpha (TNF-) include adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade).

Other biologic DMARDs included in the review target immune system components other than TNF-. They are:

Abatacept (Orencia): Its target of activity is CD28.Anakinra (Kineret): Its target of activity is interleukin 1.Rituximab (Rituxan): Its target of activity is CD20.Tocilizumab (Actemra, RoActemra): Its target of activity is the interleukin-6 receptor.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.Rating the Strength of Evidence From the Comparative Effectiveness ReviewThe Evidence-based Practice Center GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as high (further research is very unlikely to change the confidence in the estimate of effect), moderate (further research may change the confidence in the estimate of effect and may change the estimate), low (further research is likely to change the confidence in the estimate of effect and is likely to change the estimate), or insufficient (evidence either is unavailable or does not permit a conclusion). The authors also independently evaluated the applicability to real-world practice of the total body of evidence within a given clinical indication by using the PICOTS (population, intervention, comparator, outcome, timing, and setting) framework.

References:Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 10(12)-EHC063-EF. Chapters available at www.effectivehealthcare.ahrq.gov/methodsguide.cfm.

Brozek J, Oxman A, Schnemann H, for the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADEpro [computer program]. Version 3.2 for Windows. Available at www.ims.cochrane.org/revman/other-resources/gradepro/gradepro.Clinically Significant Outcomes of Interest in the Comparative Effectiveness ReviewIn analyzing the clinical study evidence, reviewers focused on these outcomes of benefit and corresponding assessment instruments or scoring indices:

- Disease activity and symptoms were evaluated using American College of Rheumatology response scores (ACR 20/50/70) and DAS and DAS28 disease activity scores.- Radiographic changes were measured using the Sharp/van der Heijde Method (SHS) for scoring radiographs.- Functional capacity was evaluated by the Health Assessment Questionnaire (HAQ) and the disability index of HAQ (HAQ-DI).- Quality of life was measured using the SF-36 and EQ-5D questionnaires.

Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI InternationalUniversity of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.Summary of Benefits: Comparative Effectiveness of Oral DMARDs for Rheumatoid ArthritisThe comparative benefits of oral disease-modifying anti-rheumatic drugs (DMARDs) may be summarized as follows:

- Leflunomide and methotrexate (MTX; 7.5 to 25 mg/week) have similar effects on symptom response, radiographic change, and functional capacity. The strength of evidence for this finding is low.- Leflunomide may be superior to sulfasalazine for improving functional capacity. The strength of evidence for this finding is low.- Sulfasalazine and MTX (7.5 to 25 mg/week) have similar effects on symptoms, disease activity, functional capacity, and limiting radiographic changes (in patients with rheumatoid arthritis for

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