Efficacy and safety of anakinra for the treatment of rheumatoid arthritis: an update of the Oregon Drug Effectiveness Review Project

Figures & data

Table 1 Administration and dosing

Drug	Mechanism	Route	Dose
Abatacept	CTLA 4-Ig	IV	Adult: dosed according to body weight (<60 kg = 500 mg; 60–100 kg = 750 mg; >100 kg = 1000 mg); dose repeated at 2 weeks and 4 weeks after initial dose, and every 4 weeks thereafter Pediatric: for children ≥6 years and <75 kg dose is 10 mg/kg, repeat dose at 2 and 4 weeks after initial infusion, and every 4 weeks thereafter. For children ≥6 years and >75 kg the dose is 750 mg if child is 75–100 kg; dose is 1000 mg if child >100 kg
Adalimumab	TNF inhibitor	SQ	RA: 40 mg every other week; patients not taking methotrexate may increase to 40 mg per week for adalimumab monotherapy PsA, AS: 40 mg every other week Plaque psoriasis: initial 80 mg as a single dose; maintenance dose is 40 mg every other week beginning 1 week after initial dose Crohn’s disease: initial dose of 160 mg given as 4 injections on day 1 or over 2 days, then 80 mg 2 weeks later (day 15); Maintenance dose is 40 mg every other week beginning day 29 Pediatric: 15 kg to <30 kg: 20 mg every other week; ≥30 kg: 40 mg every other week
Alefacept	CD2 antagonist	IM	15 mg given once weekly, treatment should be continued for 12 weeks; re-treatment with an additional 12 week course may be initiated provided that CD4+ T lymphocytes counts are >250 cells/μL and a 12-week interval has passed since the end of the initial treatment cycle
Anakinra	IL-1 receptor antagonist	SQ	RA: 100 mg once daily; dose maybe decreased to 100 mg every other day in cases of renal impairment
Certolizumab pegol	TNF inhibitor	SQ	RA: Initial dose is 400 mg, repeat dose 2 and 4 weeks after initial dose. Maintenance dose is 200 mg every other week. May consider maintenance dose of 400 mg every 4 weeks Crohn’s disease: Initial dose is 400 mg, repeat dose 2 and 4 weeks after initial dose. Maintenance dose is 400 mg every other week
Etanercept	TNF inhibitor	SQ	RA, PsA, AS: 25 mg twice weekly or 50 once weekly Plaque psoriasis: Initial dose of 50 mg twice weekly, 3–4 days apart, maintain initial dose for 3 months, Maintenance dose is 50 mg once weekly Pediatric: 0.8 mg once weekly or 0.4 mg twice weekly (maximum of 50 mg)
Golimumab	TNF inhibitor	SQ	RA, PsA, AS: 50 mg once per month
Infliximab	TNF inhibitor	IV	RA: 3 mg/kg at 0, 2, and 6 weeks followed by maintenance every 8 weeks thereafter; may increase to maximum of 10 mg/kg every 4 weeks AS: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 6 weeks thereafter Plaque psoriasis: 5 mg/kg at 0, 2, and 6 weeks, then every 8 weeks thereafter Ulcerative colitis: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter Pediatric Crohn’s disease: 5 mg/kg at 0, 2, and 6 weeks, followed by a maintenance dose of 5 mg/kg every 8 weeks; if no response by week 14, consider discontinuing therapy
Natalizumab	Alpha 4 integrin blocker	IV	Crohn’s disease: 300 mg infused over 1 hour every 4 weeks
Rituximab	Anti-CD 20a	IV	RA: 1000 mg on days 1 and 15 in combination with methotrexate

Abbreviations: AS, ankylosing spondylitis; CTLA 4-Ig, cytotoxic T-lymphocyte antigen 4; TNF, tumor necrosis factor; IL-1, interleukin-1; CD, cluster of differentiation; IM, intramuscular; IV, intravenous; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SQ, subcutaneous.

Table 2 Eligibility criteria

Population	Adult outpatients with rheumatoid arthritis
Intervention	Anakinra alone or in combination with other DMARDs or biologics
Comparison	Placebo or other biologic
Outcomes	Health-related outcomes (eg: quality of life, response) Harms (adverse events, discontinuation due to adverse events)
Study design and timing (efficacy)	Controlled trial, ≥12 weeks study duration, N ≥ 30
Study design and timing (safety)	Observational study, >6 months, ≥100 participants

Abbreviation: DMARD, disease-modifying antirheumatic drug.

Figure 1 Disposition of the literature.

Abbreviation: DERP, oregon drug effectiveness review project.

Table 3 Summary of anakinra (AKA) efficacy studies

Author	Study design, N, duration	Comparisons	Outcomes	Population	Results	Quality rating
Anakinra compared with placebo
Bresnihan et al^Citation27	RCT 472 24 wks	AKA (30 mg, 70 mg, 150 mg/day) vs placebo	ACR20, Paulus crit., SJC, TJC, HAQ, Larsen score, pain (VAS), morning stiffness	>6 months active severe RA, NSAIDs, steroids <10 mg/day allowed, no other DMARDs	Significant improvement in all ACR components (SJC, TJC, disease activity, pain ESR) in 150 mg/day group compared with placebo group	Fair
Cohen et al^Citation28	RCT 419 24 wks	AKA (0.04, 0.1, 0.4, 1.0, 2.0 mg/kg/day) vs placebo	ACR20, ACR50/70, HAQ, morning stiffness	6- to 8-year history of moderate-severe RA, stable dose MTX (15–25 mg/week)	More patients in AKA 1 mg/kg had ACR20 response (42%) than placebo group (23%). More patients in AKA 1 mg/kg and 2 mg/kg groups had an improvement on HAQ and pain	Fair
Cohen et al^Citation30	RCT 501 24 wks	AKA (100 mg/day) vs placebo	ACR20, ACR50/70, HAQ, TJC, SJC	>6-month history of active RA; stable MTX regimen 10–25 mg/wk; mean disease duration: 10.5 years	Significantly more patients in AKA group achieved a response (ACR20/50/70). Decrease in TJC greater in the AKA group	Fair
Anakinra in combination with another biologic
Genovese et al^Citation30	RCT 242 24 wks	ETA (25 mg/week or 50 mg/week) plus AKA (100 mg/day) vs ETA alone	ACR50, ACR20/70, EULAR, DAS, SF-36	>6-month history of RA; >16 weeks MTX and >8 weeks stable dose MTX of 10–25 mg/week; 50% also using steroids	Overall, no significant difference in efficacy between treatment groups	Fair

Abbreviations: ACR20/50/70, American College of Rheumatology (numbers refer to percentage improvement); AKA, anakinra; ASHI, arthritis-specific health index; DAS28, disease activity score; DMARD, disease-modifying antirheumatic drug; ETA, etanercept; EULAR, European League Against Rheumatism; HAQ, Health Assessment Questionnaire; Larsen score, radiographic evaluation; MA, meta-analysis; MTX, methotrexate; RA, rheumatoid arthritis; RCT, randomized controlled trial; SF-36, Medical Outcomes Study Short Form 36 Health Survey; SJC, swollen joint count; TJC, tender joint count; V AS, visual analogue score.

Figure 2 Meta-analysis of ACR20, ACR50 and ACR70 response (anakinra vs placebo).

Figure 3 Adjusted indirect comparisons of anakinra with anti-TNF drugs for an ACR50 response.

Abbreviation: RR, relative risk.

Table 4 Summary of studies assessing adverse events

First author	Study design N Duration	Population comparison	Results	Quality rating
Bresnihan et al^Citation27	RCT 472 24 wks	>6 months active severe RA, NSAIDs, steroids <10 mg/day allowed, no other DMARDs Placebo	More patients with ISRs in AKA groups compared with placebo: 30 mg/day 50%; 70 mg/day 73%; 150 mg/day 81%; placebo 25% Infections resulting in antibiotic use in 12% placebo vs 15%–17% AKA; of the 6 patients hospitalized for infections 4 were in the AKA 150 mg/day group vs 1 each from placebo and 75 mg/day Two patients in AKA group developed a malignancy, neutropenia occurred in 3 AKA patients compared with no placebo patients	Fair
Nuki et al^Citation19	Uncontrolled extension of RCT^Citation27 309 76 weeks	Patients with RA randomized to 30 mg/day, 75 mg/day or 150 mg/day AKA	The most common AE was ISR. ISRs occurred in 72% of patients who received 75 mg/day and 80% of patients who received 150 mg/day over the 76 week study 30% AKA withdrew from study, 14% withdrew due to AEs	Fair
Cohen et al^Citation28	RCT 419 24 weeks	6- to 8-year history of moderate-severe RA, stable dose MTX (15–25 mg/week) placebo	ISRs reported more frequently in AKA 1 mg/kg and 2 mg/kg groups (64% and 63%) compared with placebo 28% Five patients in the AKA groups experienced leukopenia 13.6% (1 mg/kg/day) and 15.3% (2 mg/kg/day) withdrew due to AEs	Fair
Fleischmann et al^Citation4 Schiff et al^Citation6 Tesser et al^Citation5 Fleischmann et al^Citation33	RCT with open-label follow-up 1399 RCT 6 months Open-label 3 years	>3 month active RA; stable NSAIDs, steroids, DMARDs dose placebo	Rate of ISRs significantly higher in AKA group compared with placebo (72.6% vs 32.9%) At 6 months, there were more serious infections in AKA group (2.1%) vs placebo (0.4%) not statistically significant; after 3 years the exposure adjusted event rates were AKA 5.4/100 patient-years vs placebo 1.6/100 patient-years The event rate for pneumonia occurred was 1.28 per 100 patient-years After 3 years of therapy, incidence rates for melanoma and lymphoma were higher than expected for the general population	Fair
Cohen et al^Citation29	RCT 501 24 weeks	>6 months history of active RA; stable MTX regimen; mean disease duration: 10.5 years. placebo	65% of patients in the AKA groups experienced ISR compared with 24% in the placebo group	Fair
Genovese et al^Citation30	RCT 242 24 weeks	>6-month history of RA; stable dose MTX; approx 50% also using steroids AKA combined with ETA vs ETA alone	More patients receiving AKA in addition to ETA experienced AEs, including ISR and serious infections, compared with ETA alone	Fair
Langer et al^Citation36	Case series efficacy–166 safety –454 up to 6 months	Patients with RA receiving AKA; population-based	Rate of adverse events was similar to those reported in efficacy trials 42.2% of patients experienced AEs: 20.7% had ISRs; 4.2% serious AEs; 5.1% infectious episodes.	Fair
Listing et al^Citation34	Prospective cohort study 1529 Up to 12 months	Infections in patients with RA treated with AKA, ETA, INF, DMARDs (German RABBIT cohort)	70 patients received open-label AKA. Those that received a biologic had more severe disease than the control patients receiving a DMARD Infections were observed in 13% of AKA patients compared to 6% of control patients AEs occurred at a rate of 17.5/100 patient-years for AKA Serious AEs occurred at 3.2/100 patient-years	Fair
Zink et al^Citation35	Prospective cohort study 1523 12 months	Patients with RA treated with AKA, ETA, INF (German RABBIT cohort)	Of the 70 patients receiving AKA, 41% discontinued treatment within 12 months: 16.3% discontinued due to AEs; 29.6% discontinued due to lack of efficacy i n comparison, 31.4% of patients receiving ETA and 34.6% of patients receiving INF discontinued therapy within 12 months	Fair

Abbreviations: ACR 20/50/70, American College of Rheumatology (numbers refer to percentage improvement); ADA, adalimumab; AE, adverse event; AKA, anakinra; ASHI, arthritis-specific health index; DAS28, disease activity score; DMARD, disease-modifying antirheumatic drug; ETA, etanercept; EULAR, European League Against Rheumatism; HAQ, Health Assessment Questionnaire; ISR, injections site reaction; MA, meta-analysis; MTX, methotrexate; RA, rheumatoid arthritis; RCT, randomized controlled trial; SF-36, Medical Outcomes Study Short Form 36 Health Survey; SJC, swollen joint count; TJC, tender joint count.

Appendix 1 Anti-TNF biologic studies included for indirect comparisons with anakinra

Author	Study design	N	Duration	Comparisons	Primary outcome	Population
Furst et al^Citation1	RCT	636	24 weeks	ADA + Standard RA therapy/Placebo + Standard RA therapy	Safety	Active RA for at least 3 months; DMARD naïve/or on stable regimen; mean disease duration: 10.5 years.
Keystone et al^Citation2	RCT	619	52 weeks	ADA + MTX/Placebo + MTX	Sharp, ACR 20, HAQ	Active RA; on stable MTX regimen; mean disease duration: 11 years.
Kim et al^Citation3	RCT	128	24 weeks	ADA + MTX/MTX	ACR 20	Active RA; had failed at least 1 DMARD treatment; mean disease duration: 6.9 years.
Miyasaka et al^Citation4	RCT	352	24 weeks	ADA/Placebo	ACR 20	Active RA; had failed at least 1 DMARD treatment; mean disease duration: 9.5 years.
Van de Putte et al^Citation5	RCT	284	12 weeks	ADA/Placebo	ACR 20	Active RA; had failed at least 1 DMARD treatment; mean disease duration: 10 years.
Van de Putte et al^Citation6	RCT	544	26 weeks	ADA/Placebo	ACR20	Active RA; had failed at least 1 DMARD treatment; mean disease duration: 11 years.
Weinblatt et al^Citation7	RCT	271	24 weeks	ADA + MTX/MTX + Placebo	ACR20, HAQ	Active RA; stable MTX regimen; had failed at least 1 other DMARD; mean disease duration: 12 years.
Klareskog et al^Citation8	RCT	682	52 weeks	ETA/MTX/MTX + ETA	Sharp	>6 months active RA; ACR functional class I–III; unsatisfactory response to at least 1 DMARD other than MTX; mean disease duration: 6.5 years.
Lan et al^Citation9	RCT	58	12 weeks	ETA + MTX/Placebo + MTX	Number of swollen/tender joints	Active RA > 1 year; stable MTX for 4 weeks; mean disease duration: NR
Moreland et al^Citation10	RCT	180	12 weeks	ETA/Placebo	Number of swollen/tender joints	Active RA; failed 1 to 4 DMARD treatments; mean disease duration: NR
Moreland et al^Citation11,^Citation12	RCT	234	12 weeks	ETA/Placebo	ACR 20/50	Active RA; failed 1 to 4 DMARD treatments other than MTX; mean disease duration: 12 years.
Weinblatt et al^Citation13	RCT	89	24 weeks	ETA + MTX/Placebo + MTX	ACR 20	Active RA; >6 months MTX, stable >1 month; mean disease duration: 13 years
Abe et al^Citation14	RCT	147	14 weeks	INF + MTX/Placebo + MTX	ACR 20	>6 months history of active RA; mean disease duration 7.9 years.
Kavanaugh et al^Citation15	RCT	28	12 weeks	INF + MTX/Placebo + MTX	ACR 20	RA < 15 years; MTX > 3 months; mean disease duration 4.9 to 7.5 years.
Maini et al^Citation16	RCT	43	26 weeks	INF + MTX/Placebo + MTX	Paulus 20	MTX > 6 months; mean disease duration 7.6 to 114.3 years.
Maini et al^Citation17	RCT	428	30 weeks	INF + MTX/Placebo + MTX	ACR 20	MTX stable >4 weeks; mean disease duration 7.2 to 9.0 years.
Westhovens et al^Citation18	RCT	1084	22 weeks	INF + MTX/Placebo + MTX	ACR 20	Active RA despite MTX treatment; median disease duration: 15 years.
Zhang et al^Citation19	RCT	173	18 weeks	INF + MTX/MTX	ACR 20/50/70	Adult outpatients with active RA and insufficient response to standard antirheumatic therapy.

Abbreviations: ACR20/50/70, American College of Rheumatology (numbers refer to percentage improvement); DMARD, disease-modifying antirheumatic drug; ETA, etanercept; HAQ, Health Assessment Questionnaire; MTX, methotrexate; N, number; NR, not reported; RA, rheumatoid arthritis; RCT, randomized controlled trial.

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