Consensus statement Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i2 INTRODUCTION As in previous years, the consensus group to con- sider the use of biological agents in the treatment of rheumatic diseases met during the 12th Annual Workshop on Advances in Targeted Therapies in April 2010. The group consisted of rheumatologists from a number of universities among the conti- nents of Europe, North America, South America, Australia and Asia. Pharmaceutical industry support was obtained from a number of companies for the annual workshop itself but these companies had no part in the decisions about the specific programme or about the academic participants at this con- ference. Representatives of the supporting spon- sors participated in the initial working groups to supply factual information. The sponsors did not participate in the drafting of the consensus statement. This consensus was prepared from the perspec- tive of the treating physician. In view of the new data for abatacept, B cell- specific agents, interleukin 1 antagonists (IL-1), tocilizumab and tumour necrosis factor α (TNFα) blocking agents, an update of the previous con- sensus statement is appropriate. To allow ease of updating, the 2008 updates (March 2009–February 2009) have been incorporated into the body of the manuscript, while 2010 updates (March 2009– February 2010) are separated and highlighted. The consensus statement is annotated to document the credibility of the data supporting it as much as pos- sible. This annotation is that of Shekelle et al and is described in an appendix. 1 We have modified the Shekelle annotation by designating all abstracts as ‘category D evidence’, whether they describe well-controlled trials or not, as details of the study were often not available in the abstracts. Further, the number of possible references has become so large that reviews are sometimes included; if they contain category A references, they will be referred to as category A evidence. The rheumatologists and bioscientists who attended the consensus conference were from 23 countries and were selected for their expertise in the use of biological agents for the treatment of rheumatic diseases. The number of attendees and participants was limited so that not everyone who might have been interested could be invited. All participants reviewed a draft document developed by the coauthors, based on a review of all relevant clinical published articles relating to abatacept and rituximab (B-cell-specific therapy) as well as IL-1 blocking agents, tocilizumab and TNFα blocking agents. The draft was discussed in small working groups. The revisions suggested by each group were discussed by all participants in a final open session and this led to a final document, represent- ing this updated consensus statement. It is hoped that this statement, which is based on the best evidence available at this time and is modified by expert opinion, will facilitate the optimal use of these agents for patients with conditions approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA) for clinical use. Extensive tables of the use of these agents in non-registered uses are included as appendices, to help experienced doc- tors to use these drugs in exceptional (‘off-label’) circumstances. GENERAL STATEMENTS The formatting of this document is arranged as follows: general introduction and general state- ments followed by each biological agent arranged by generic name or general mechanism (when appropriate). Within each biological agent, the data are arranged by indication, the information is arranged according to clinical use, such as dosing, time to response, etc. Some combination of indi- cations occurs when appropriate safety is arranged together after clinical use, in alphabetical order. Individual patients differ in the clinical expres- sion and aggressiveness of their disease, its con- comitant structural damage, the effect of their disease on their quality of life (QoL) and the symp- toms and signs engendered by their disease. They also differ in their risk for, and expression of, side effects to drugs. All these factors must be exam- ined when considering biological treatment for a patient, as must the toxicity of previous and/or alternative disease-modifying antirheumatic drug (DMARD) use. As increasing evidence has accumulated on the efficacy and clinical use of biological agents for the treatment of psoriatic arthritis (PsA) and anky- losing spondylitis (AS), these diseases will be dis- cussed separately from rheumatoid arthritis (RA). Adverse reactions, unless disease specific, however, will remain combined for all indications. In general, in RA, when measuring response to treatment or when following up patients over For numbered affiliations see end of article Correspondence to Professor D E Furst, David Geffen School of Medicine, UCLA – RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA; [email protected]Accepted 2 December 2010 Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010 D E Furst, 1 E C Keystone, 2 J Braun, 3 F C Breedveld, 4 G R Burmester, 5 F De Benedetti, 5 T Dörner, 5 P Emery, 6 R Fleischmann, 7 A Gibofsky, 8 J R Kalden, 9 A Kavanaugh, 10 B Kirkham, 11 P Mease, 12 J Sieper, 12 N G Singer, 13 J S Smolen, 14 P L C M Van Riel, 15 M H Weisman, 16 K Winthrop 17 group.bmj.com on March 28, 2011 - Published by ard.bmj.com Downloaded from
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Consensus statement
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i2
INTRODUCTIONAs in previous years, the consensus group to con-sider the use of biological agents in the treatment of rheumatic diseases met during the 12th Annual Workshop on Advances in Targeted Therapies in April 2010. The group consisted of rheumatologists from a number of universities among the conti-nents of Europe, North America, South America, Australia and Asia.
Pharmaceutical industry support was obtained from a number of companies for the annual workshop itself but these companies had no part in the decisions about the specifi c programme or about the academic participants at this con-ference. Representatives of the supporting spon-sors participated in the initial working groups to supply factual information. The sponsors did not participate in the drafting of the consensus statement.
This consensus was prepared from the perspec-tive of the treating physician.
In view of the new data for abatacept, B cell-specifi c agents, interleukin 1 antagonists (IL-1), tocilizumab and tumour necrosis factor α (TNFα) blocking agents, an update of the previous con-sensus statement is appropriate. To allow ease of updating, the 2008 updates (March 2009–February 2009) have been incorporated into the body of the manuscript, while 2010 updates (March 2009– February 2010) are separated and highlighted. The consensus statement is annotated to document the credibility of the data supporting it as much as pos-sible. This annotation is that of Shekelle et al and is described in an appendix.1 We have modifi ed the Shekelle annotation by designating all abstracts as ‘category D evidence’, whether they describe well-controlled trials or not, as details of the study were often not available in the abstracts. Further, the number of possible references has become so large that reviews are sometimes included; if they contain category A references, they will be referred to as category A evidence.
The rheumatologists and bioscientists who attended the consensus conference were from 23 countries and were selected for their expertise in the use of biological agents for the treatment of rheumatic diseases. The number of attendees and participants was limited so that not everyone who might have been interested could be invited. All participants reviewed a draft document developed by the coauthors, based on a review of all relevant
clinical published articles relating to abatacept and rituximab (B-cell-specifi c therapy) as well as IL-1 blocking agents, tocilizumab and TNFα blocking agents. The draft was discussed in small working groups. The revisions suggested by each group were discussed by all participants in a fi nal open session and this led to a fi nal document, represent-ing this updated consensus statement.
It is hoped that this statement, which is based on the best evidence available at this time and is modifi ed by expert opinion, will facilitate the optimal use of these agents for patients with conditions approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA) for clinical use. Extensive tables of the use of these agents in non-registered uses are included as appendices, to help experienced doc-tors to use these drugs in exceptional (‘off-label’) circumstances.
GENERAL STATEMENTSThe formatting of this document is arranged as follows: general introduction and general state-ments followed by each biological agent arranged by generic name or general mechanism (when appropriate). Within each biological agent, the data are arranged by indication, the information is arranged according to clinical use, such as dosing, time to response, etc. Some combination of indi-cations occurs when appropriate safety is arranged together after clinical use, in alphabetical order.
Individual patients differ in the clinical expres-sion and aggressiveness of their disease, its con-comitant structural damage, the effect of their disease on their quality of life (QoL) and the symp-toms and signs engendered by their disease. They also differ in their risk for, and expression of, side effects to drugs. All these factors must be exam-ined when considering biological treatment for a patient, as must the toxicity of previous and/or alternative disease-modifying antirheumatic drug (DMARD) use.
As increasing evidence has accumulated on the effi cacy and clinical use of biological agents for the treatment of psoriatic arthritis (PsA) and anky-losing spondylitis (AS), these diseases will be dis-cussed separately from rheumatoid arthritis (RA). Adverse reactions, unless disease specifi c, however, will remain combined for all indications.
In general, in RA, when measuring response to treatment or when following up patients over
For numbered affi liations see end of article
Correspondence toProfessor D E Furst, David Geffen School of Medicine, UCLA – RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA; [email protected]
Accepted 2 December 2010
Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010D E Furst,1 E C Keystone,2 J Braun,3 F C Breedveld,4 G R Burmester,5 F De Benedetti,5
T Dörner,5 P Emery,6 R Fleischmann,7 A Gibofsky,8 J R Kalden,9 A Kavanaugh,10
B Kirkham,11 P Mease,12 J Sieper,12 N G Singer,13 J S Smolen,14 P L C M Van Riel,15
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(category C evidence12). Abatacept has been used with MTX and other DMARDs. (category A, B evidence10 11 13–17).
Juvenile idiopathic arthritisAbatacept is recommended for treatment of active polyarticu-lar juvenile idiopathic arthritis (JIA) as monotherapy or with DMARDs after an adequate trial of MTX. In the USA, it is approved after the use of another effective DMARD as well (category C evidence18 19).
In Europe, abatacept in combination with MTX is indicated for the treatment of moderate to severe polyarticular JIA in patients 6 years and older who have insuffi cient response to other DMARDs, including at least one TNFα blocking agent.
Clinical useDosingRheumatoid arthritis
The adult dosing regimen is 750 mg or 1000 mg given at 0, 2 and 4 weeks then monthly, intravenous (FDA product label).
Time to responseSome patients respond to abatacept, using the American College of Rheumatology response criteria, within 2–4 weeks. Most adult patients respond within 12–16 weeks of starting treat-ment. (It may take longer in children—see below (category A evidence19 20.) Patients continue to improve for up to 12 months (category A evidence7 8 21). QoL and other patient- related outcomes, such as sleep, fatigue and activity, also improve (category A evidence22).
Cost-effectivenessAbatacept appears cost-effective and comparable to other bio-logical agents (category B effective14 23–26).
PersistenceSome patients maintained response on abatacept for up to 3 (TNF-incomplete responders (TNF-IR)) to 5 years (MTX-incomplete responders (MTX-IR)) in long-term open-label extension studies (category C evidence24 27).
Comparison with TNFα blocking agentsIn a controlled trial, the clinical effi cacy of abatacept (10 mg/kg) was similar to low dose infl iximab (3 mg/kg); these were numeri-cally fewer serious adverse events in the abatacept treated patients (category A evidence28).
Structural changesAbatacept in combination with MTX inhibits or reduces radio-graphic progression in RA in MTX-IR patients (category A, B and C evidence24 29–31).
In MTX naïve early RA patients, MTX plus abatacept was superior to MTX plus Placebo (category A evidence27).
Juvenile idiopathic arthritisDosingAbatacept is administered as intravenous infusions of 10 mg/kg for weights <75 kg; 750 mg for weights of 75–100 kg and 1000 mg for weights >100 kg. All regimens are given intravenously at 0, 2 and 4 weeks, then monthly (FDA product label)) (category A evidence19).
Time to responseWhile most patients with JIA respond within 16 weeks of starting treatment, some children may take 3–6 months or longer before their maximal response is achieved (category A evidence19 20).
time, validated quantitative measures for clinical trials can be used, such as Disease Activity Score, Simplifi ed Disease Activity Index, Clinical Disease Activity Index, RAPID, Health Assessment Questionnaire Disability Index (HAQ-DI), visual analogue scales (VAS) or Likert scales of global response or pain by the patient, or global response by the doctor. Other validated measures for individual patient care, joint tenderness and/or swelling counts and laboratory data may all be used and may be appropriate measures for individual patients (category A, B2– 8). The doctor should evaluate a patient’s response using one of the above instruments to determine the patient’s status and change.
For PsA, measures of response such as joint tenderness and swelling, enthesitis and dactylitis, global and pain response measures, functional indices and acute phase reactants, both as single measures and as part of composite measures have been used.2 4 9
For AS, measures such as the Bath Ankylosing Spondylitis Disease Activity Index and the Bath Ankylosing Spondylitis Functional Index are used; they have been used in clinical tri-als but have not been validated for routine clinical practice (category C evidence).5 In this disease, clinical measures such as joint tenderness and swelling, spinal motion, global and pain response measures, functional indices and acute phase reactants have been used and are validated.
Pregnancy remains a controversial topic when using biologi-cal agents in the rheumatic diseases. For all but the TNFα and IL-1 blocking agents, there are too few data to draw any conclu-sions. Since a lack of association is extremely diffi cult to prove, no biological agent can be assumed to be safe. In the absence of such data, this recommendation depends on the USA-FDA designation. Abatacept and tocilizumab have a category C des-ignation while TNFα and IL-1 blocking agents are designated as category B (see specifi c drugs).
The appropriate use of biological agents will require doc-tors experienced in the diagnosis, treatment and assessment of RA, PsA, AS and other rheumatic diseases who are aware of the data regarding long-term observations of effi cacy and toxic-ity, including cohort studies and data from registries. Because biological agents have adverse effects, patients or their repre-sentatives should be provided with information about potential risks and benefi ts so that they may give informed consent for treatment. To enable ease of reference, the biological agents are listed in alphabetical order: abatacept; B-cell therapy; IL-1 block-ing agents; tocilizumab; TNF blocking agents.
ABATACEPTOne agent which modulates T-cell activation (abatacept) has been approved in the United States and Europe.
IndicationsRheumatoid arthritisAbatacept is recommended for treatment of active RA as monotherapy or with DMARDs in moderate to severe adult RA after an adequate trial of methotrexate (MTX) or another effective DMARD (in the USA). In early RA abatacept has been approved in North America in MTX-naïve patients in combina-tion with MTX6 (category A evidence7 8 10 11). Abatacept had been approved by the EMA for active RA after an inadequate response to a non-biological DMARD and a failure of at least one TNFα blocking agent.
Abatacept may be administered at the time when the next dose of the TNFα blocking agent would normally be given
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Based on theoretical concerns, live vaccines should not be given while a patient is receiving abatacept or within 3 months
of using abatacept.2010 Update:Pregnancy—There have been too few cases of preg-
nancy when using abatacept for any defi nite conclusion to be drawn. See general statement on page i2. According to the US FDA, abatacept is considered category C, meaning ‘No human studies and animal studies either show risk or are lacking. However, potential benefi ts may justify potential risks.’
RITUXIMAB B-CELL THERAPYRituximab is a chimeric anti-CD20 monoclonal antibody which
was approved in 1997 for treatment of indolent CD20, B-cell
non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukaemia.
A consensus statement on the use of rituximab in patients
with RA has been published (category D evidence40).
IndicationsRheumatoid arthritisRituximab has been approved by the FDA in the USA for the treatment of moderate-to-severe RA, with MTX, in patients for whom at least one TNFα blocking agent has produced an inade-quate response (category A and D evidence41–43) (FDA and EMA label; category C and D evidence44–49). It may also be used when TNFα blockers are not suitable (category D evidence50–52).
A greater rate of American College of Rheumatology responses was seen with rituximab in rheumatoid factor/anti-cyclic cit-rullinated peptide-positive patients who were DMARD non-responders (category C evidence44 46) and in non-responders to TNFα blocking agents (category D evidence44 50 53 54).
Clinical useDosingRituximab is administered intravenously as two 1 g or two 500 mg rituximab infusions (given with 100 mg methylpred-nisolone or equivalent) separated by an interval of 2 weeks. These doses are equivalent clinically, although the higher dose retards radiographic measures better than the lower dose (category A evidence41 44 47–49 55 56). In RA, it may be used alone or in combination with MTX or other DMARDs (category A and D evidence41–43 52 53 56), although the optimal treatment schedule remains under further investigation (cat-egory D evidence41 46 50 53).
Time to responseIn clinical trials, rituximab results in signifi cant improvement in signs and symptoms and/or laboratory measures by 8–16 weeks (category A, D evidence56–63).
PersistenceRituximab is effective over up to 5 years in patients with an inadequate response to MTX for whom conventional DMARDs have failed or who have used one or more TNF inhibitors (cat-egory A, B evidence41 56 60 62–65).
2010 Update:Studies have shown that repeated treatment courses
are effective in previously responsive patients with RA (category C, D evidence61 64). Open-label extension stud-ies of up to 6 years showed continued response (cate-gory D evidence66). Most of the patients who received subsequent courses did so 24 weeks or more after the
SafetyAutoimmune diseaseNo increased incidence of autoimmune diseases was noted in the abatacept clinical trial database (category D evidence32).
InfectionsTuberculosis
All patients in abatacept phase III trials were screened for tubercu-losis (TB) with a tuberculin skin test (TST) but were still included if the screen was positive and they were treated for latent TB. Cases of TB were observed in the clinical trial programme (cat-egory C, D evidence23 33). The risk for reactivation of latent TB or for developing new TB when using abatacept is unknown. Until the risk is known, it is appropriate to screen patients considered for abatacept therapy for TB according to local practice.
Serious infections
Patients with chronic obstructive pulmonary disease (COPD) treated with abatacept had more serious lower respiratory tract infections than patients treated with placebo; therefore its use in patients with RA and COPD should be undertaken with caution.
In comparison with placebo in clinical trials, the incidence of serious infections with abatacept was increased in trials at 12 months but not in a meta-analysis pooling 6- and 12-month safety data (category A evidence33 34). In a review of clinical trial data, the incidence of hospitalisations for infections remained stable for up to 5 years and the incidence was not signifi cantly different in the long-term extension as compared with the blinded phase of clinical trials (3.0 vs 2.1/100 000 patient-years). As with the other such trials, the uncontrolled cohort design with observed data limits the generalisability of these data (cat-egory C evidence33).
For abatacept in combination with other biological agents, the rate of serious infections is 4.4% (vs 1.5% in controls) (cat-egory C evidence15). The use of abatacept with a TNFα blocking agent is not recommended, as an increased incidence of serious infections was noted when the combination was used (category A evidence35 36). There are no data about the combination of abatacept and rituximab.
MalignanciesOne case of a lymphoma occurred in a double-blind trial with abatacept versus none in the placebo group; four additional cases occurred in the open-label extension (cumulatively 5/4134 patient-years), while an epidemiological overview showed no increase (category B, D evidence32 37). Although this number is consistent with that expected from large RA cohorts, continuing surveillance is necessary. When abata-cept clinical trial data were compared with national registries, no increased rates of lymphoma, lung, breast, colorectal or total malignancies were found, although the control popula-tions were not entirely comparable (category D evidence32). Epidemiological experience in six RA cohorts showed no increased rate of solid malignancies compared with the RA cohorts (category D evidence37), although continued monitor-ing is necessary. (category C evidence37)
VaccinationsThere was a decreased response to infl uenza, tetanus and pneumococcal vaccinations when using abatacept in healthy volunteers (category C evidence38). Infl uenza and pneumococ-cal vaccinations in patients with RA receiving abatacept were reduced, comparable to previous reports in patients with RA receiving MTX (category D evidence39).
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Severe infectionsSimilar to TNFα blockers and other biological agents, a small increase in serious bacterial infections was seen in patients receiving rituximab. There was no increase in the incidence of serious infectious events with up to nine courses of treatment (category A, D evidence46 66 77)
No increase in the rate of serious infections was seen in a cohort of 259 patients who received another biological agent after rituximab treatment compared with patients receiv-ing rituximab treatment before a biological agent (category D evidence78).
Baseline immunoglobulin levels were generally normal in
patients entering clinical studies, and decreased levels of IgM, IgA and IgG have been seen with rituximab. In clinical tri-als, no increase in serious infections has been reported in the patients with reduced levels of IgM after rituximab treatment compared with their previously normal IgM levels (category B evidence47 53).
After repeated courses of rituximab, a proportion of patients develop IgG levels below the lower limit of normal. Those patients have demonstrated a numerical increase in infections in open studies (category C, evidence66). This increase has not been confi rmed by open-label extension studies for patients with initial normal IgG levels. In contrast, patients with IgM and IgA below the limit of normal before rituximab treatment are a patient group at highest risk (category C evidence79).
B-cell levels have been measured in clinical trials but their importance in routine practice has not been proved. Depletion of the CD20+ B-cell subpopulation by routine measures was not predictive of achieving or maintaining a clinical response in
patients with RA (category D evidence48 80–85). This suggests that
the timing of re-treatment should be based on disease activity.
2010 Update:In a small open randomised study of rituximab in com-
bination with adalimumab or etanercept, no signifi cant increase of serious infectious events over 6 months was observed (category C evidence86)
Infusion reactionsThe most widespread adverse events are infusion reactions, which are most common with the fi rst infusion of the fi rst course (up to 35%) and are reduced with the second and subse-quent infusion (about 5–10%). Intravenous corticosteroids were shown to reduce the incidence and severity of infusion reac-tions by about 30% without changing effi cacy (category A, C and D evidence41 42 44 46 51–53). Rare anaphylactoid reactions have occurred when rituximab is used (category C evidence).
MalignanciesThere is no evidence that rituximab is associated with an increased incidence of solid tumours in RA. Nevertheless, vigi-lance for the occurrence of solid malignancies remains warranted during treatment with rituximab (category B evidence66).
Neurological syndromesCases of progressive multifocal leucoencephalopathy (PML)
have been seen in patients with systemic rheumatic diseases with and without rituximab treatment (FDA communication). Three cases reported to regulatory agencies of PML in patients with RA treated with rituximab have been reported. The causal relationship between PML and rituximab remains unclear.
2010 Update Pregnancy:See general statement on page i2. According to the
US FDA, rituximab is considered category C, ‘no human
previous course and none received repeated courses ear-lier than 16 weeks after the previous course (category B, D evidence65 66). Treatment with rituximab every 6 months demonstrated better clinical effi cacy than on- demand treatment without signifi cantly increasing adverse events (category B evidence65). There are con-fl icting data on the effi cacy of re-treatment of initial non-responders (category C evidence67).
Degree of responseIn a retrospective non-randomised open-label study,68 and in an observational study comprising 2500 patients,69 70 patients for whom one or more TNFα blocking agent had failed (owing to ineffectiveness) switching to rituximab or another TNFα blocker and rituximab was more effective than using another TNFα blocking agent.
Improvement has also been demonstrated in patient-related outcomes such as HAQ-DI, patient global VAS, fatigue, disabil-ity and QoL (category A, evidence71 72). Data from randomised controlled trials (RCTs) show that the combination of rituximab with MTX yields better clinical effi cacy for RA than monother-apy (category A evidence42 46 51 60). Preliminary data of non-inter-ventional studies69 70 suggest that combination with lefl unomide yields even higher responses than with MTX.
Structural changesRituximab inhibits radiographic progression in both MTX-naïve patients and in those for whom one or more TNFα blocking agent has produced an inadequate response (category A evi-dence). In RA, at 1 year, rituximab in combination with MTX, the 1000 mg×2, regimen, reached the primary end point of pro-tection against radiographic progression compared with MTX alone (category B evidence73).
SafetyHepatitis
Rituximab treatment is normally contraindicated in hepatitis B since fatal hepatitis B reactivation has been reported in patients with NHL treated with rituximab. In the case of occult or of latent hepatitis B virus, alanine aminotransferase (ALT) should be measured regularly and if elevated hepatitis B virus DNA is found, should be checked with sensitive assays.74 Hepatitis B status should be assessed before treatment.
Rituximab has been used in hepatitis C virus (HCV)-associated cryoglubulinaemic vasculitis (category A, D evidence75 76). Data are not available in HCV-infected patients with RA who have cryoglobulinaemia and rituximab appears effective and safe in these case reports.
Infections (see also ‘Neurological syndromes’ below)TuberculosisIn general, patients who did not respond to TNF inhibitors will
also have been prescreened for the presence of active or latent
TB. In the RA clinical trials of rituximab in TNFα non-responders, patients with active TB were excluded. Others were screened by chest radiograph examination, but were not screened for latent TB by purifi ed protein derivative testing. There is no evidence of an increased incidence of TB in patients with NHL treated with rituximab. There are insuffi cient data to make a determination about the necessity to screen for TB before starting treatment. Thus, the clinician should be vigilant for the occurrence of TB during treatment.
Rituximab should not be given in the presence of serious or
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cold autoinfl ammatory syndrome/familial cold urticaria (cat-egory A, C evidence107–109). These are all rare conditions due to mutations in the NALP3 gene, in which a major role for IL-1 has been shown. The effi cacy of rilonacept and canakinumab has been shown in placebo-controlled randomised clinical trials (category A evidence97 98). Canakinumab is indicated in the USA and Europe in adults, adolescents and children with CAPS aged ≥4 years with a body weight >15 kg. Rilonacept is indicated in the USA and Europe in adults and adolescents with CAPS aged ≥12 years (category A, C evidence97 98 107 108).
Anti-IL-1 agents have prompt, major and sustained clinical benefi t in CAPS.97 98 107–109 Canakinumab is administered sub-cutaneously every 8 weeks at a dose of 150 mg for patients with body weight >40 kg and at 2 mg/kg for patients with body weight >15 kg and <40 kg. No dose adjustment is needed in patients with end-stage renal disease (category C evidence110). Rilonacept is administered subcutaneously once a week at a dose of 160 mg for patients >18 years and at 2.2 mg/kg for patients between 12 and 18 years of age. There is no evidence that one agent is more effective than another in CAPS.
JIA and adult-onset Still’s diseaseIL-1β signalling pathway blockade with anakinra is effective in a proportion of patients with systemic-onset JIA and adult-onset Still’s disease (see Table A.3 for additional references).
ANKYLOSING SPONDYLITIS AND PSAAnakinra has been evaluated in two open-label studies of AS, but without consistent evidence of effi cacy.582 583 Anakinra did not demonstrate clinical effi cacy in PsA.584
CRYSTAL-ASSOCIATED ARTHROPATHIESThere are anecdotal reports of clinical effi cacy following treatment with anakinra in patients with intractable gout585 and pseudogout.586
OTHER ARTHROPATHIESTreatment with intra-articular anakinra was evaluated in a ran-domised clinical trial of patients with osteoarthritis (category A evidence587). Treatment was well tolerated but no improve-ments were observed compared with placebo.
Anakinra has been used with effect in CAPS, familial Mediterranean fever, the TNF receptor-associated periodic syn-drome, defi ciency of the interleukin-1-receptor antagonist and Schnitzler syndrome.
Clinical useTiming of responseAnakinra can lead to signifi cant improvement in symptoms, signs and/or laboratory parameters of RA within 16 weeks and can inhibit or induce slowing of radiographic progression (cat-egory A evidence99 102 103 111). If improvement is not seen by 16 weeks, discontinuation of anakinra should be considered.
Comparison with TNFα blocking agents2010 Update:A recent meta-analysis demonstrates that anakinra is
less effective than the TNFα inhibitors in treating RA (cat-egory A evidence90)
SafetyThese agents have largely been established in patients with RA receiving anakinra. Use of newer drugs (canakinumab or rilonacept) or use in non-approved indications may disclose other safety concerns (category A, C evidence98 110).
studies and animal studies either show risk or are lacking. However, potential benefi ts may justify potential risks.’
Because of the possible B-cell depletion in the fetus after rituximab, it is recommended that it be discontinued 1 year before a planned pregnancy.87 88
There have been too few cases of pregnancy when using rituximab for any conclusion about their use during pregnancy.89 90 The antibody, as an IgG, is excreted with milk.
Skin reactionsRare reports of psoriasis, including severe cases and rare instances of vasculitis,91 have been reported in patients with RA, systemic lupus erythematosus and NHL after rituximab treatment (cat-egory D evidence92 93). The causative role of rituximab in these circumstance remains unknown.
VaccinationIn a controlled trial, rituximab signifi cantly decreased the immune response to neoantigen, (keyhole limpet haemocya-nin) and pneumococcus, whereas delayed-type hypersensitivity responses and responses to tetanus were unchanged (category A evidence94).
2010 Update:Humoral responses to infl uenza vaccination in patients
with RA were severely reduced shortly after rituximab administration but modestly restored at 6–10 months. Importantly, patients with a previous annual infl uenza vaccination were more likely to develop protective titres to vaccination, suggesting that all patients should receive yearly vaccination (category B evidence95). No data are available on the success of vaccination against infl uenza after several courses of rituximab.
Since rituximab causes B-cell depletion, it is recommended that any vaccinations required by the patient, such as those to prevent pneumonia and infl uenza, should be given before start-ing treatment. (category A evidence96). Until further data are available, the use of live attenuated vaccines should only be given before the use of rituximab.
IL-1 BLOCKING AGENTSOne IL-1-blocking agent, anakinra (IL-1 receptor antagonist), has been approved for use in RA. Two IL-1 inhibitors, rilonacept (IL-1 Trap) and canakinumab (anti-IL-1β monoclonal) have been approved for use in cryopyrin-associated periodic syndromes (CAPS) (category A evidence97–101).
IndicationsRheumatoid arthritisAnakinra may be used for the treatment of active RA, alone or in combination with MTX, at a dose of 100 mg/day subcutane-ously (category A evidence102–104). In Europe, the anakinra label requires prescription in combination with MTX. Anakinra is rec-ommended for the treatment of active RA after an adequate trial of non-biological DMARDs or with other DMARDs (category A evidence,99 100 105 category C evidence106). No trials of anakinra as the fi rst DMARD for patients with early RA have been published.
Cryopyrin-associated periodic syndromesRilonacept and canakinumab have major clinical benefi t in children and adults with CAPS, including severe familial cold autoinfl ammatory syndrome, Muckle–Wells syndrome and neonatal-onset multisystem infl ammatory disease/chronic infantile neurological cutaneous, articular syndrome, familial
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lack of response) to DMARDs or TNFα inhibitors (category A, D evidence120–125 132–138). The FDA has approved tocilizumab for use in patients with moderate to severe RA who are incomplete responders to TNF-antagonist agents (category D evidence135–138). In Japan tocilizumab is approved in patients with RA for whom one or more DMARDs produces insuf-fi cient response (category A, D122 138).
JIA and other indicationsIn Japan and India, tocilizumab has also been approved for sys-temic JIA based on a small open 19-patient study of systemic- onset JIA and multicentric Castleman’s disease (category A evi-dence132 139 140).
Clinical useTocilizumab reduces signs and symptoms of active RA in incomplete responders to DMARDs or TNFα blocking agents (category A evidence120–124). In many countries tocilizumab can be used as monotherapy in DMARD/MTX-naïve patients (cat-egory A, D evidence124 136 141) or DMARD inadequate respond-ers (category A, D122 138).
DosingThe dosing regimens recommended vary by indication and country so they are shown in Table 1. Tocilizumab is admin-istered intravenously monthly in a dose of 4 or 8 mg/kg. In general, 8 mg/kg has been found to be more effective than 4 mg/kg (see table below). In combination with MTX or other DMARDs, it can be used at 4 or 8 mg/kg although 4 mg/kg monotherapy was less effective in DMARD incomplete responders (category A evidence120–125 132). Tocilizumab use and dosing have not yet been approved for use in children by the FDA or EMA.
2010 Update:The 2010 update is shown in Table 1.Tocilizumab has been used in JIA-associated arthritis (class A evidence134).
Timing of responseOnset of response can occur as early 2–4 weeks in some patients but it may take ≥24 weeks in other patients (cat-egory A, D evidence122 123). Biomarkers (IL-6) have been used as a predictor of response (category D evidence142 143). Tocilizumab can be restarted after long-term withdrawal (category D evidence144)
Comparison with TNFα blocking agentsTocilizumab has not been compared directly with TNFα block-ing agents. It can be used after failure of one or more TNFα inhibitor (category A, D evidence123 137).
Structural changesTocilizumab inhibits or reduces radiographic progression in patients for whom MTX or other DMARDs have produced an inadequate response (category A125 145 146) and it also inhibits or
InfectionsTuberculosisTo date, there is no indication that use of anakinra is associated
with an increased incidence of TB (category D evidence77).
Bacterial infectionsThe incidence of serious bacterial infections was increased in patients receiving anakinra and the incidence was higher than in patients with RA using non-biological DMARDs. The increased incidence of infection was greatest in patients who were also receiving corticosteroids or >100 mg/day anakinra (category A evidence104 112). Patients should not start or con-tinue anakinra if a serious infection is present (category A evidence104 112 113). Treatment with anakinra in such patients should only be resumed if the infection has been adequately treated.114– 117 Anakinra has been used to treat macrophage activation syndrome, which may be triggered by JIA or by infection (category D evidence118)
When anakinra was used in combination with etanercept, there was no increase in effi cacy. However, an increase in the incidence of serious infection was observed in comparison with either compound used as monotherapy. Therefore, the combi-nation of anakinra and etanercept should not be prescribed (cat-egory A evidence114).
Injection site reactionsA dose-related incidence of injection site reactions, affecting
up to 70% of patients, has been reported with the use of anak-inra. These reactions often do not require treatment and seem to moderate with continued use in most patients (category A evidence99 102 119).
PregnancySee general statement on page i2. According to the USA FDA, anakinra is considered category B—that is, no evidence of risk in humans. If no adequate human studies are done; no animal studies have been done; or animal studies show risk but human studies do not.
VaccinationsIn one controlled trial, anakinra did not inhibit antitetanus anti-body response (category D evidence111).
TOCILIZUMABTocilizumab is a humanised anti-IL-6 receptor monoclonal anti-body (category A, D evidence120–126).
IndicationsRheumatoid arthritisTocilizumab has been approved in the European Union and a number of other countries in combination with MTX (cat-egory A, B, C evidence127–131). It is approved as monotherapy for the treatment of moderate to severe active RA in adults who are incomplete responders (owing to adverse events or
Table 1 Tocilizumab: Dosing regimens and 2010 update EMA area* FDA area Japan*
RA 8 mg/kg every 4 weeks 4 mg/kg every 4 weeks initially, with an increase to 8 mg/kg every 4 weeks if clinically indicated
8 mg/kg every 4 weeks
Polyarticular JIA139 – – 8 mg/kg every 4 weeksSystemic onset JIA – – 8 mg/kg every 2 weeks (interval may be decreased to weekly)Multicentric Castleman’s disease140 – – 8 mg/kg every 2 weeks (interval may be decreased to weekly)
* In the EMA area and Japan, it can also be used as monotherapy in patients with contraindications to, or intolerant of methotrexate.EMA, European Medicines Agency; FDA, Food and Drug Administration; JIA, juvenile idiopathic arthritis.
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InfectionsBacterial infectionsIn a 6-month controlled clinical study, the rate of serious infec-tions in the 4 and 8 mg/kg arms were numerically higher in the tocilizumab then placebo+DMARD arms (4.4 and 5.3/100 patient-years compared with 3.9/100 patient-years) The rates were stable over time in open-label extensions of controlled tri-als (category D evidence126 148 155 163 172). Tocilizumab should not be given when serious or opportunistic infections are present (category D evidence132). As with other biological agents, care-ful observation for bacterial infections is necessary (category B, D evidence148 154 155 163 164).
2010 Update:In a 24-week randomised clinical trial involving 678 patients,
serious infections were twice as common with tocilizumab (1.4%) as MTX alone (0.7%) (category B evidence175).
The downregulatory effect of tocilizumab on the acute-phase reactant, C-reactive protein (CRP), may limit the usefulness of CRP as a diagnostic indicator for infections.
TB and opportunistic infectionsCases of TB and opportunistic infections have been observed in patients taking tocilizumab (EMA; category A, D evidence164 176 177). Patients should be screened for (latent) TB before treatment. See ‘TNF antagonist’ section for details of TB screening.
Viral infectionsCases of localised H zoster infection have occurred in clinical tri-als, but it is not clear whether H zoster is increased in association with tocilizumab (category D evidence164 169).
2010 Update:No instances of active hepatitis B or C were found, but
patients were excluded from trials if they had positive hepatitis B or C serologies.
Infusion-related eventsSerious infusion reactions during/after treatment with tocili-zumab are uncommon (category A, D178)
MalignanciesThere is no evidence that tocilizumab therapy is associated with an increased incidence of malignancies in patients with RA (cat-egory A, D evidence120–125 141 148). Systematic safety surveillance should be performed during tocilizumab treatment similar to requirements for other biological agents.
2010 Update (pregnancy):There have been too few cases of pregnancy when using
tocilizumab for any conclusions to be drawn (category C89).See general statement on page i2. According to the US
FDA, this drug is considered category C, meaning ‘no human studies and animal studies either show risk or are lacking. However, potential benefi ts may justify potential risks.’
SkinErythroderma has been ascribed to tocilizumab (category D evidence179).
TNFΑ BLOCKING AGENTSTNFα blockers differ in composition, precise mechanism of action, pharmacokinetics and biopharmaceutical properties, but this document emphasises areas of commonality. Studies that
have clearly differentiated between compounds will be dis-cussed, where appropriate.
reduces radiographic progression as monotherapy (category A evidence133 145).
SafetyCardiovascular end points and lipid levels
The overall long-term effect of tocilizumab on cardiovascular outcomes is at present not known. In a follow-up for up to 5 years (category D evidence141 147–153), there was no apparent increase in cardiac event rates. Hypertension and cerebrovascular accidents (CVAs) have been seen (category A, D evidence132 141
148 154–157). In a follow-up with a median of 1.5 years, no increase in the rate of CVAs was found (category D evidence158)
Increases in mean fasting plasma lipid levels, including total cholesterol, low-density lipoprotein, triglycerides and high-den-sity lipoprotein, were seen in 20–30% of tocilizumab-treated patients (category A, D evidence148 154 155 159 160). Lipid levels should be monitored 1–2 months after initiation of treatment and then every 6 months. It should be managed according to local recommendations.
Initiation of statin therapy after receiving tocilizumab is effec-tive in reducing lipids (category D evidence161).
Gastrointestinal
In 6-month controlled clinical trials, generalised peritonitis, lower gastrointestinal perforation, fi stulae and intra-abdominal abscesses have been reported (overall rate 0.26/100 patient-years compared with no events in the control arm). The concomitant use of corticosteroids and non-steroidal anti-infl ammatory drugs may increase the risk of these events. Tocilizumab should be used with caution in patients with a history of intestinal ulcer-ation or diverticulitis (category D evidence162).
Haematological
Neutropenia A higher proportion of patients treated with tocili-zumab had a decrease in the absolute neutrophil count compared with placebo. A few patients had a decrease of polymorpho-nuclear cells to <1000 cells/mm3 and, rarely, <500 cells/mm3. This change usually occurs early after a dose and is transient. Complete blood counts should be monitored regularly accord-ing to local labels (usually every 4–8 weeks). In one study, there was an accompanying increase in infections but this was not seen in most studies (category A, D evidence163–168).
VaccinationSafety and response to vaccinations were evaluated in patients with RA receiving tocilizumab. Most patients could be effec-tively immunised with infl uenza and pneumococcal vaccine (category D evidence169). As for the other biological agents, live vaccines should not be given while patients are receiving tocili-zumab (category A, D evidence132 148 164 170 171).
Hepatic aminotransferase and bilirubin elevations
ALT and aspartate aminotransferase (AST) elevations occurred with similar frequency with tocilizumab monotherapy compared with MTX alone (category A evidence172–174). For tocilizumab in combination with DMARDs, including MTX, elevations are more common than with tocilizumab alone. Elevations of bili-rubin, mostly indirect and sometimes associated with Gilbert’s syndrome, occur separately and are not associated with hepatic dysfunction. Liver function should be monitored regularly.
Recommendations for the management of tocilizumab-related laboratory abnormalities have been included in the EMA and FDA package which are consistent with those for MTX. No instances of tocilizumab-induced hepatic fail-ure or liver damage have been documented (category A, D evidence120–125 132–134 141 148 154–156 163 164 169 172–174).
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level (category A, B evidence197 232 240–243). The addition or substi-tution of other DMARDs may increase effi cacy in some patients.
Timing of response
TNFα blocking agents, when administered up to the maximum approved dosing regimens for RA and polyarticular JIA, may elicit response in 2–4 weeks in some patients. They usually lead to signifi cant, documentable improvement in symptoms, signs and/or laboratory parameters within 12–24 weeks (category A and B evidence90 113 115 116 180–196 199 201 205 223–225 231 232 239 242 244–253). Clinically signifi cant important responses, including patient-oriented measures (eg, HAQ-DI, patient’s global VAS, Medical Outcome Survey Short Form 36) and physical measures (eg, joint counts), should be demonstrated within 12–24 weeks for RA (category A evidence90 113 115 116 181–190 192 194 195 196 199 201 203 223–225
228 244 245–247 250 251). For patients in remission or with low disease activity, anecdotal studies indicate that lowering the dose may be successful without loss of effect (category C evidence113 115 183 184
188 197–202 254).If improvement occurs, treatment should be continued. If
patients show no response to these agents, their continued use should be re-evaluated. Etanercept weekly dosing in children (0.8 mg/kg up to 50 mg weekly) also improves health-related QoL and reduces disease activity.255
Comparison of TNFα blocking agents
There is no evidence that any one TNFα blocking agent should be used before another can be tried. There is also no evidence that any TNFα blocking agent is more effective than any other in RA (category A and B evidence25 26 30 38 49 113 176 181 191 239 243 248 252 256 257).
2010 Update:A recent meta-analysis contended that etanercept was
safer than anakinra, adalimumab or infl iximab (category A evidence243).
Persistence
In long-term observational studies, some patients continue to respond for up to 10 years. (category C evidence176).
Loss of response to a TNFα blocking agent can occur. Failure to respond to one TNFα blocking agent does not preclude response to another (category B, D evidence239 248 252 256 257). Patients have been switched successfully from one TNFα block-ing agent to another. Several retrospective and observational studies suggest the effi cacy of such switches. One recent RCT supports this regimen (category B, D evidence24 258 259 260).
Information from observational data suggests that primary
non-responding patients are less likely to respond to a sec-ond TNFα blocking agent. Patients who have not tolerated one TNFα blocking agent may respond to a second but are also more likely to have less tolerance of it (category B and D evidence248 261 262 263). Patients who have responded to a TNFα blocking agent but have lost response may respond to a second TNFα blocking agent . The optimal treatment of patients not responding to TNFα blockers remains to be determined (cat-egory C evidence141 181 184 189 199 224 232 264).
Patients with high or moderate disease activity at base-line can respond well to TNFα blocking agents (category C evidence264 265).
Structural changes
TNFα blocking agents inhibit or reduce radiographic progres-sion in RA, even in some patients without a clinical response (category A evidence113 115 117 181 185 187 190 211 247 251 266–269). Better clinical and radiological outcomes are achieved when TNFα
IndicationsRheumatoid arthritisIn most patients, anti-TNFα agents are used in conjunction with another DMARD, usually MTX. TNFα blockers have also been used successfully with other DMARDs, including sulfa-salazine and lefl unomide. TNFα blocking agents are effective for the treatment of RA in MTX-naive patients (category A, D evidence90 113 115 116 180–193). A TNFα blocker can be used as the fi rst DMARD in some patients (category A evidence90 113 117 180–189 194; category A, B evidence35 116 117 123 186 190 195–197). Adalimumab, cer-tolizumab, etanercept and golimumab are approved as mono-therapy for RA. Infl iximab is only approved for use with MTX in RA. However, observational data indicate that infl iximab, too, is sometimes used as monotherapy (category C evidence198–200). The combination of a TNFα blocking agent and MTX yields bet-ter results for RA than monotherapy, particularly with respect to excellent clinical responses and radiological outcomes (category
A evidence90 113 115 180–192 194 195 198–203).Preliminary data indicate that a triple combination of tradi-
tional DMARDs is clinically as effective as a combination of MTX plus etanercept (category A evidence158).
Psoriatic arthritisBased on the demonstration of control of signs and symptoms of joint and skin disease, improvement of function, QoL and inhi-bition of structural damage, the available TNFα blocking agents (adalimumab, etanercept, golimumab and infl iximab) have been widely approved for the treatment of patients with PsA for whom conventional treatments have produced an inadequate response. Effi cacy has been demonstrated both as monotherapy and with background MTX. (category A, B evidence147 170 171 204–222).
Ankylosing spondylitisAdalimumab, etanercept, golimumab and infl iximab have been widely approved for the treatment of active AS that is refractory to conventional treatments. In clinical trials, the effi cacy of these TNFα blocking agents improved signs and symptoms, function and QoL as monotherapy as well as with concomitant second-line agents, including sulfasalazine or MTX (category A, B evi-dence196 223–231). There is no evidence that combination therapy with conventional DMARDs is better than monotherapy.A recent randomised controlled trial demonstrated no superi-ority of a combination of MTX with infl iximab versus infl ix-imab alone in the treatment of active AS over 1 year (category B evidence771).
Juvenile idiopathic arthritisEtanercept and adalimumab have been approved for JIA with a polyarticular course (FDA: ≥2 years for etanercept; ≥4 years for adalimumab; EMA: age 13–17 years for both) (category A, B evidence232–239) FDA and EMA approvals) Infl iximab was benefi cial at 6 mg/kg in polyarticular JIA (category A evidence232 233 238 239).
2010 UpdateA recent meta-analysis of RCTs demonstrated that
etanercept, infl iximab and adalimumab were more effec-tive than anakinra in RA (category A evidence122).
Clinical useRheumatoid arthritisDosing
Increasing the dose or reducing the dosing intervals of infl iximab may provide additional benefi t in RA, whereas increased doses of etanercept or certolizumab have no increased benefi t at a group
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for PsA based on a systematic evidence-based review of the effi -cacy of TNFα blocking agents.216
In addition to effi cacy in joints and skin, effi cacy has been demonstrated with TNFα blocking agent therapy for enthesi-tis, dactylitis, function, QoL fatigue, productivity, work dis-ability and inhibition of structural damage (category A, B, D evidence170 171 204 206 210 211 213 215 217–222 234 287 288 289–293).
Dose and timing of response
Improvement of signs and symptoms, function and QoL occurs within 12 weeks. Some patients continue to improve up to week 24. For etanercept, 100 mg a week for 12 weeks, fol-lowed by 50 mg a week, was more effective than 50 mg a week for skin but not arthritis, enthesitis or dactylitis (category D evidence294).
2010 Update:In children with PsA, maximal response to etanercept
may take longer than 3 months (category C evidence235).
Comparison of TNFα blocking agents in PsA
A recent meta-analysis of randomised controlled trials suggests that the effi cacy of TNFα antibodies may be better than that of soluble receptor with respect to skin manifestations (category A evidence292).
Switching between TNFα blocking agents in PsA
Preliminary data suggest that one can sometimes achieve benefi t for PsA-related joint and skin signs and symptoms by switching to a different TNFα blocking agent, even if effi cacy from a previous TNFα blocker was never achieved (category C evidence293).
Persistence
Durability of clinical effi cacy and radiographic data up to 2 years in PsA has been demonstrated with etanercept, infl iximab and adalimumab (category A, B, C evidence220 221).
2010 UpdateGolimumab 50 and 100 mg given once monthly shows
similar clinical effi cacy for up to 104 weeks.The golimumab and certolizumab safety profi le is simi-
lar to that seen for other anti-TNF agents (category B evidence290 295 296).
Ankylosing spondylitisIn clinical trials in patients fulfi lling the modifi ed New York crite-ria for AS, improvement in signs and symptoms were seen after treatment with TNFα blocking agents using patient- reported
outcomes (Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, patient global VAS, Short Form 36)), spinal mobility measures, peripheral arthritis, enthesitis and acute phase reactants (category A, B, D evidence196 223–227 231 297–308). Two recent placebo-controlled trials have shown signifi cant effi cacy in signs and symptoms in patients with non-radiographic axial spondyloarthritis (category A, D evidence299 302) according to the Assessment of Spondylo-Arthritis International Society criteria for axial spondyloarthritis (category A evidence298).
Clinical use
Two RCTs failed to demonstrate superiority of a combination of MTX with infl iximab over infl iximab alone in the treatment of active AS over 1 year (category B evidence72 196 223). Regular treatment with infl iximab was more effective than ‘on-demand’ treatment for AS (category A evidence309 310).
Observational studies indicate that switching to a second TNFα blocking agent may be effective (category B, C evidence306 311).
blockers are used in combination with a traditional DMARD (category A evidence270).
Pharmacoeconomic data
TNFα blocking agents may be cost effective from a societal per-spective, although this is highly dependent upon the specifi c cir-cumstances of the analysis and the society in which the analysis is done (category B evidence120 182 271–281).
2010 Update in RA:Golimumab and certolizumab pegol have been recently
approved for the treatment of RA and demonstrated effi -cacy in clinical trials similar to that of other TNFα block-ing agents in improving signs and symptoms, physical function, health-related QoL and reducing252 256 257 the radiographic progression of patients with RA (category A evidence282–285). The adverse event profi le is consistent with that of other TNFα blockers.
Recent data on absenteeism or presenteeism as well as work productivity have supported the effectiveness of TNFα blocking agents.7 13 15 22
Juvenile idiopathic arthritisDose
TNFα blocking agents, when given up to the maximum approved dosing regimens for polyarticular JIA, usually lead to an early sig-nifi cant, documentable improvement in symptoms, signs and/or laboratory parameters. Etanercept weekly dosing in children (0.8 mg/kg up to 50 mg weekly) also improves health-related QoL and reduces disease activity (category B evidence255).
Comparison of TNFα blocking agents in JIA
Etanercept appears less effective in patients with systemic-onset JIA than in patients with other forms of JIA (category C evidence234–237). There are now ongoing prospective studies in children aged <4 years; however, some observational registry data suggest comparable effi -cacy and safety in JIA not of the systemic-onset subtype, Except for systemic-onset JIA, there is no evidence that any one TNFα blocking agent should be used before another one can be tried for the other JIA subtypes (category D evidence234). In JIA-associated uveitis, adalimumab and infl iximab appear to be effective more often than etanercept (category C, D evidence286 287).
2010 Update:Some observational registry data suggest comparable
effi cacy and safety in polyarticular JIA as in the systemic-onset subtype (category C evidence235 236).
Switching TNFα blocking agent
Anecdotal studies indicate that TNFα blocking agents may be successfully switched in JIA (category D evidence237 238).
Persistence
In one small open study, remission occurred in 24% of patients with systemic JIA but 45% fl ared when the TNFα blocking agent was stopped (category C evidence234).
Structural changes
TNFα blocking agents contribute to restoration of growth veloc-ity in children whose JIA-associated infl ammation is controlled. Bone density improves after treatment with a TNFα blocking agent even in patients who have incomplete disease control (cat-egory C, D evidence234–238).
Psoriatic arthritisThe Group for Research and Assessment of Psoriasis and Psoriatic Arthritis has developed treatment recommendations
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Antibodies directed against adalimumab or infl iximab have been correlated with decreased clinical response in some patients with AS. This was not found for etanercept (category C evidence311 318–321). Acute phase reactions correlate with response (category B evidence313 314).
The importance of adding regular physical therapy to TNFα blocking agents has been highlighted in a recent observational trial (category C evidence322).
Safety (arranged alphabetically) across indicationsGeneral reviews of the safety of TNFα blocking agents have been published (category A, B evidence86 90 113 181 184 189 243 251
305 306 323).
Autoimmune-like syndromes
Antiphospholipid and lupus-like syndromes have occurred in both adult and paediatric patients during treatment with TNFα blocking agents. Autoantibody formation is common after TNFα blocker therapy (eg, antinuclear antibodies), but clinical syndromes associated with these antibodies are rare (category C evidence282 283).
Cardiovascular
Treatment of non-RA patients with advanced chronic heart fail-ure with TNFα blockers was associated with greater morbidity/mortality (infl iximab) or lack of effi cacy (etanercept). Studies that
examined the risk of heart failure in patients with RA treated
with TNFα blockers have shown inconsistent results (category B evidence261 262 323).
On the other hand, several studies showed decreased cardio-vascular events (myocardial infarction, stroke or transient ischaemic attack) (category D evidence261 324 325). Results of studies evaluating the effect of TNFα blocking agents on lipids are confl icting (category D evidence318–320 326–329).
2010 UpdateA review (category C evidence262 330) and multiple open
studies of TNFα blocking agents have been published (category C, D evidence329–333). Infl iximab, etanercept and golimumab are reported to improve lipid and arthro-genic profi les, reduce arterial stiffness and decrease insu-lin resistance in comparison with controls. No long-term studies regarding CVA or death have appeared (category C, D evidence261 262 318 319 324 326–328 330–336). One long-term study demonstrated that a reduction in myocardial infarc-tions was found (category C evidence324 336). To date these profi les seem to refl ect the degree to which infl ammation is controlled. Better disease control was refl ected in either unchanged or improved lipid profi les, whereas incom-plete control was associated with worsening profi les. The clinical signifi cance of these changes on cardiovascular symptoms is unknown.
Haematological
Rare instances of pancytopenia and aplastic anaemia have been
reported (category C evidence262 323). If haematological adverse events occur, TNFα blocking agents should be stopped and patients evaluated for evidence of other underlying diseases or association with concomitant drugs.
Transaminase elevation
Elevated liver function tests have been observed in patients treated with adalimumab and infl iximab, with ALT/AST increased in 3.5–17.6% and increased more than twice the upper limit of normal in up to 2.1 % (category B, D evidence263 337). The use of concomitant drugs and other clinical conditions confound
2010 Update:In a head-to-head comparison trial of a conventional
DMARD (sulfasalazine) with a TNFα blocking agent (etanercept), the latter was more effective (category A evidence246 312).
There is evidence that the incidence of uveitis fl ares is reduced when patients are treated with TNFα blocking agents. There is a trend for TNFα antibodies to reduce the frequency of uveitis episodes more than etanercept (category A evidence286 287).
Young patients with active AS and raised CRP levels responded better to TNFα blocking agents than older patients without such markers (category A evidence196 301 303 313 314). However, even in patients with advanced and severe AS, there is evidence that TNFα blocking agents can be effi cacious (cat-egory D evidence303 315).
Dosing
The approved doses of TNFα blocking agents for treatment of AS are 5 mg/kg infl iximab intravenously every 6–8 weeks after induction; subcutaneous etanercept, 25 mg twice a week or 50 mg once a week; 50 mg subcutaneous golimumab monthly and 40 mg adalimumab subcutaneously every other week (category A and B evidence223 224 225 299 316). No dose-ranging studies have been done with most of these drugs, except for golimumab, where no major differences in effi cacy and safety between 50 mg and 100 mg doses were seen (category B evidence217).
Time to response
Although improvement may be seen more rapidly, a reduc-tion in signs and symptoms and improvement in function and QoL will usually be seen by 6–12 weeks in response
to treatment with a TNFα blocking agent (category A evidence231 309 312).
Comparison of TNFα blocking agents in AS
There is no evidence that any TNFα blocking agent is more effective for musculoskeletal symptoms in AS than any other (category A, B, D evidence196 223–227 231 297–308).
Persistence
TNFα blocking agents (adalimumab, etanercept, infl iximab) maintained effi cacy for 2–7 years in open-label studies. The dis-ease usually fl ares after discontinuation of the blocking agent (category C evidence298 301–304). When TNFα blocking agents are restarted, treatment response reoccurs in over 70% (category C evidence303).
Imaging changes
Several studies have shown that active infl ammation of the sacroiliac joints and spine, as shown by MRI, is signifi cantly reduced for up to 3 years by adalimumab, etanercept, infl iximab and golimumab (category A, B, C evidence302 304 311 316).
Patients with AS who received TNFα blocking agents showed signifi cant increases in bone mineral density scores (category C evidence297 298).
Pharmacoeconomic data in AS
The use of TNFα blocking agents may be cost effective in patients with active AS (category B evidence317).
2010 Update in patients with AS:The Assessment of Spondylo-Arthritis International
Society has updated its recommendations for the use of TNFα blocking agents in AS (category C evidence231 297 298).
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recommendations (category B, C and D evidence). In areas of high TB prevalence (ie, high-risk populations or in the event of potential TB exposure) repeat screening should be considered. (category C evidence349 364 365).
The TST is a diagnostic aid and false-negative results can occur in the setting of immune suppression (eg, HIV, renal dialysis,
corticosteroid use and RA) (category C evidence276). The TST
can also be falsely positive due to previous BCG vaccination. New blood-based diagnostic assays (interferon γ release assays)
have been developed using TB-specifi c antigens. These tests
(Quantiferon-Gold In-tube and T-Spot TB) have greater specifi c-ity for latent TB infection than the TST and therefore might pro-vide a useful tool in evaluating people for latent TB (particularly
those with history of BCG vaccination). It should be noted that false-negative results and indeterminate results also occur with the interferon γ release assays (category C evidence366 367). The background rate of TB in the population should be considered in the interpretation of these tests.
The precise role of these tests in diagnosing latent TB in patients with rheumatoid disease remains under study (category C evidence361).
Repeat screening should be performed in the event of TB exposure and should be considered in patients who are at ongo-ing risk for TB exposure (eg, living or extended travel to endemic areas (category C evidence349). Local screening guidelines should be followed. Continued vigilance is required to detect reactiva-tion of latent TB or acquisition of new cases.
In treating latent TB, the optimal time frame between starting
preventive treatment for latent TB infection and starting TNFα blocking agents is unknown. Given the low numbers of bacilli
present in latent TB infection, it is likely that long time periods between initiating preventive treatment and TNF blockade is unnecessary. Although there are no prospective trials assessing
this question, observational data from Spain suggest that initi-ating isoniazid therapy 1 month before TNF blockade substan-tially decreases the risk of latent TB reactivation. (category C evidence276 362 363). Before starting preventive anti-TB treatment in accordance with local guidelines, consultation with an infec-tious disease specialist should be considered.
2010 Update:There are case reports of reinitiation of TNFα blocking
agents after successful completion of a full course anti-TB therapy (category C evidence368).
Other opportunistic infectionsOther opportunistic infections have been reported in patients treated with TNFα blocking agents (category C evidence90 113 265 369 370–373). Particular vigilance is needed when considering patients with infec-tions whose containment is macrophage/granuloma dependent, such as those with listeriosis, non-tuberculous mycobacteria (category D evidence361 372), coccidiomycosis or histoplasmosis (including reacti-vation of latent histoplasmosis) (category C and D evidence90 113 370
371 373).A British registry study found that the rate of intracellular
infections among patients with RA treated with TNFα blocking agents was 200/100 000 and signifi cantly higher than in similar patients treated with DMARDs or corticosteroids (category C and D evidence357 369).
Bacterial infectionsSerious bacterial infections (usually defi ned as bacterial infec-tions requiring intravenous antibiotics or hospitalisation) have also been seen in patients receiving TNFα blocking agents at rates between 0.07 and 0.09/patient-year compared with 0.01–0.06/patient-year in controls using other DMARDs (category C
the interpretation of this observation (FDA; category B and C evi-dence289 337 338–342). The follow-up and monitoring for increases in liver function test should be governed by the patient’s concomi-tant drugs, conditions and patient-related risk factors. Worsening of alcoholic hepatitis has been seen in patients receiving TNFα blocking agents (category C evidence337).
2010 Update:Golimumab and certolizumab, like the other TNFα
blocking agents, are subject to liver function test eleva-tions (category A, C, D evidence295 343–348).
InfectionsTuberculosisAn increased susceptibility for TB or reactivation of latent TB has been reported for all TNFα blocking agents (category A,B,C evidence275 276 295 349–368). The risk of TB is also increased by the use of corticosteroids. There appears to be a higher incidence of TB in patients using the monoclonal antibodies, infl iximab and adalimumab, as compared with etanercept (category B, C, D evidence350 352–354). Although this difference may be due, in part, to differences in mechanism of action, biology or kinet-ics as compared with the soluble receptor (category C, D evi-dence295 350–365), it may also be, in part, due to the fact that populations treated with the various TNFα blocking agents differ (eg, higher background rates of TB in some countries) and the data come from registries and voluntary reporting systems.
The clinical manifestations of active TB may be atypical in
patients treated with TNFα blocking agents (eg, miliary or extra pulmonary presentations) as has been seen with other immuno-compromised patients (category C evidence358 359 360).
2010 Update:Two recent, large observational studies from the United
Kingdom and France have reported the rates of TB reac-tivation in patients using adalimumab or infl iximab to be signifi cantly higher than in patients using etanercept (cat-egory C evidence353 354).
TB risk data for golimumab and certolizumab are lim-ited. Trials of golimumab exclude patients with active or latent TB and cases of TB were uncommon (category B evi-dence295). In trials of certolizumab there was an increased incidence of TB relative to controls, but TB screening pro-cedures were not standardised among sites (category C evidence176).
In the United States, an area with low TB prevalence, the majority of mycobacterial infections among TNFα blocker users were caused by non-tuberculous mycobacteria, with only 35% mycobacterium TB. M avium was as frequently found as M tuberculosis, and multiple other non-tuberculous mycobacte-rial infections accounted for the rest of the mycobacterial infec-tions (category C evidence361).
Screening of patients about to start TNFα blocking agents has
reduced the risk of reactivating latent TB for patients treated
with these agents (category B evidence362 363). Every patient should be evaluated for the possibility of latent TB, including a history that should comprise seeking a history of prior expo-sure, prior drug addiction or active drug addiction, HIV infec-tion, birth or extended living in a region of high TB prevalence and a history of working or living in TB high-risk settings such as jails, homeless shelters and drug rehabilitation centres (cat-egory B evidence275 358).
In addition, physical examination and screening tests such as
TSTs and chest radiographs should be carried out before treat-ment with TNFα blocking agents is started, according to local
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i13
A recent observational study reported a small increase risk of herpes zoster with monoclonal antibodies, while another observational study found no increase in risk with anti-TNF therapy as a whole and reported signifi -cantly lower risks for etanercept and adalimumab than for infl iximab (category D and B evidence277 377).
Injection site/infusion reactionsIn placebo-controlled trials, injection site reactions, most of which were mild to moderate (but some of which resulted in
drug discontinuation) were more common with subcutaneously administered TNFα blocking agents than with placebo (category A, B evidence90 113 117 181 265 305 323). One study indicated that
human antichimeric antibodies against infl iximab were associ-ated with decreased response and increased infusion reactions (category C evidence285).
Acute reactions after adalimumab, golimumab administra-tion are uncommon and are usually mild to moderate, but may, rarely, be serious (category A, B evidence113 180 188 226 347 378). In most instances, infusion reactions can be treated by the use of corticosteroids or antihistamines, or by slowing the infusion rate (category B and C evidence278 285 379).
2010 Update:Golimumab and certolizumab are associated with a
very low incidence of injection site reactions (category B, C evidence295 348).
MalignanciesThe incidence of lymphoma is increased in chronic infl amma-tory diseases such as RA. This increase is associated with high disease activity (category C evidence315 380). In most studies the risk for lymphoma (especially non-Hodgkin’s lymphoma) is increased two- to fi vefold in patients with RA as compared with the general population (category B evidence381–386). A similar risk is seen in patients with RA who have received TNFα block-ing therapy (category A, B, C evidence315 323 380–387). It is unclear if the risk of lymphoma is increased.
While two meta-analyses (with infl iximab and adalimumab) report a higher rate of solid malignancies, including skin (cat-egory A evidence388 389), several other large observational data-bases and a case–control study did not demonstrate an increased incidence of solid tumours in patients receiving TNFα blocking agents compared with matched controls (category B, C evi-dence315 382–386 390–396).
Further studies found no increased risk of solid tumours in analyses of the same data, in which positive associations were previously found. (category A, B, C evidence394 395). Neither the duration of treatment nor the duration of follow-up were associ-ated with an increased risk of cancer during the fi rst 5 years of treatment (category B evidence392).
The evidence regarding an increased incidence of non-melan-otic skin cancers associated with TNFα blocking agents is con-fl icting (category B evidence381).
In patients with COPD, there may be an increased risk of lung cancers when treated with TNFα blocking agents. In a trial of patients with COPD assigned to infl iximab versus placebo, nine developed lung cancers during the trial and another four lung can-cers were found during an open-label follow-up (category A evi-dence396 397). Lung cancer appears to be increased in RA, although whether this is owing to disease activity or confounding factors is not known (category C evidence396 397). In a study of Wegener’s granulomatosis, the use of etanercept with cyclophosphamide was associated with six solid malignancies versus none in the cyclophosphamide placebo group (category A evidence393).
evidence112 258 259 260 268). Risk ratios of 1–3 were documented (category B, C268 269). TNFα blocking agents should not be administered in the presence of active serious infections and/or opportunistic infections, including septic arthritis, infected prostheses, acute abscess, osteomyelitis, sepsis, systemic fungal infections and listeriosis (category C evidence112 268 270).
Treatment with TNFα blocking agents in such patients may be resumed if the infections have been treated adequately (cat-egory D evidence; FDA90 112 113 258–260 268).
Other studies indicate that serious infections in certain sites, such as the skin, soft tissues and joints, are more common when using TNFα blocking agents and the risk may be highest during the fi rst 6 months of treatment. It may be increased further in elderly patients (category D evidence,270 category C evidence260).
Biological agents and high-dose corticosteroids affect acute phase reactions (eg, erythrocyte sedimentation rate, CRP) irrespective of the cause of the infl ammation. Therefore care needs to be exercised when these measures are used to help diagnose infection in the presence of these agents (category C evidence,277 278 category B evidence259 260 374).
The incidence of other bacterial infections (not designated as serious) may be increased when using TNFα blocking agents (RR=2.3–3.0, 95% CI 1.4 to 5.1) (category C evidence112 258–260 268).
The incidence of serious infections is approximately doubled when IL-1 receptor antagonist or abatacept is used with any of
the TNFα blocking agents in combination (category A evidence,
FDA35 36 198 306).The use of TNFα plus IL-1 blocking agents or abatacept in
combination is not recommended.2010 Update:Among patients with JIA in an open study, the rate of
serious infections was not different among MTX, etan-ercept and etanercept plus MTX groups (category C evidence20).
Viral infectionsHepatitis
Patients should be screened for viral hepatitis before initiation of TNFα blocking agents, as the long-term safety of these agents in patients with chronic viral hepatitis (hepatitis B and C) is not known. In patients with hepatitis C and RA, several observational studies in infected patients have shown no increased incidence of toxicity (eg, raised liver function tests or viral load) associated with TNFα block-ing agents (category C, D evidence279 289 309 339 340 341 375). Interestingly, one reported controlled trial of etanercept given adjunctively to stan-dard anti-HCV therapy was associated with signifi cant improvement in liver enzymes, viral load and symptoms (category C evidence376). In hepatitis B, patients treated with adalimumab, etanercept and inf-liximab have experienced increased symptoms, worsening of viral load and in some cases hepatic failure (especially after stopping the TNFα blocking agents ) (category C, D evidence289 339 340 342 375).
Specifi c warnings about hepatitis B reactivation have been added to the US label by the FDA. Thus TNFα blocking agents should generally not be used in patients with known persistent hepatitis B infection. If hepatitis B infection is discovered during use of TNFα blocking agents, prophylactic antiviral treatment can be employed (category C evidence376).
2010 Update:Small cases series have been reported in which
TNFα blocking agents were used in patients with evi-dence of previous hepatitis B (HBsAb positive, HBsAg and DNA negative) with only transient elevations in transaminases and no change in viral load (category D evidence340).
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i14
and no transfer of etanercept in breast milk (category D evi-dence411). These data, if corroborated will help guide advice to mothers treated with TNFα blocking agents.
Male sexual functionIn limited data, sperm volume and function were not different from normal. Men using TNFα blocking agents can father nor-mal children, and sexual function seems either unaffected or improved (category C evidence412).
PulmonaryRare instances of acute, severe and sometimes fatal interstitial
lung disease have been reported in patients using TNFα blocking agents (category C evidence413).
Skin diseaseCases of psoriasis, psoriaform lesions or exacerbation of pso-riasis have been reported when using all TNFα blocking agents. In some cases, switching TNFα blocker allowed continuation of treatment without recrudescence of skin lesions (category D evidence414–418). Additionally, rare cases of Stevens–Johnson syndrome, digital vasculitis, erythema multiforme, toxic epider-mal necrolysis granulomatous reactions in skin and lungs have been noted (category D evidence379 398 419–423). Hypersensitivity reactions to TNFα blocking agents were not associated with the atopic status of the patients, in one small study.
VaccinationsAppropriate vaccinations should be carried out before initi-ating treatment with TNFα blockers, according to national guidelines.
TNFα blocking agents do not usually adversely effect the development of protective antibodies after vaccination with infl uenza or polysaccharide pneumococcal vaccine, although there is a small decrease in the prevalence of adequate protec-tion and a decrease in the titre of response, especially in combi-nation with MTX (category A, B evidence280 281 284). Vaccination with live attenuated vaccines (eg, nasal fl u vaccine, BCG, yel-low fever, herpes zoster) is not recommended, though vaccina-tion with MMR with appropriate memory vaccine response has been reported in patients with JIA treated with etanercept and MTX (category D424).
OTHER BIOLOGICAL AGENTSAlefacept is approved in the USA for psoriasis but not PsA.
Alefacept is a fully human fusion protein that blocks interac-tion between LFA-3 on antigen-presenting cells and CD2 on T cells, leading to decreased T-cell activation and deletion of cer-tain T-cell clones. A phase II trial in PsA demonstrated modest effi cacy in joints and skin at 24 weeks (category B evidence425). A second course (each course is 12 weekly intramuscular injections followed by 12 weeks off) during an open-label extension dem-onstrated sustained articular effi cacy (category A evidence425)
Efalizumab is a humanised monoclonal antibody to the CD11 subunit of LFA-1. It has been removed from the market after cases of progressive multifocal leucoencephalopathy.
Ustekinumab is an inhibitor of IL-12 and IL-23 which acts in both the TH17 and TH1 pathways of infl ammation and is approved for the treatment of psoriasis, given at 0, 4 and then every 12 weeks subcutaneously (category B evidence426).
CONCLUSIONThe treatment of RA and other rheumatic diseases and condi-tions of altered immunoreactivity has changed dramatically for
The concomitant use of azathioprine with infl iximab in ado-lescents has been associated with the occurrence of rare hepato-splenic lymphomas (category C evidence, FDA). It is not currently known if TNF blockade worsens an underlying malignancy or increase the risk of recurrence (category B evidence384 394).
Vigilance for the occurrence of lymphomas and other malig-nancies (including recurrence of solid tumours) remains appro-priate in patients treated with TNFα blocking agents.
2010 Update:In JIA, malignancies have been reported in patients
treated with TNFα blocking agents but it is unknown if the rate of malignancy is increased compared with JIA itself. Malignancies were seen in a long-term follow up study of etanercept in JIA (category C and D evidence FDA letter and Giannini et al236).
After starting TNFα blocking agents, the risk of can-cer does not increase with time (category B, evidence392). One study has shown that monoclonal antibodies are associated with a higher risk of lymphoma than soluble receptors, but additional confounding factors need to be examined (category C evidence385).
Certolizumab was not associated with solid malig-nancies but was associated with lymphoma (category B evidence296).
Neurological diseasesRare instances of central and peripheral demyelinating syn-dromes, including multiple sclerosis, optic neuritis and Guillain–Barré syndrome, have been reported in patients using TNFα blocking agents (category C evidence398–407). In some cases, but not all, these syndromes improved after withdrawal of TNFα blockers and steroids were given. Accordingly, TNFα blocking agents should not be given to patients with a history of demy-elinating disease, multiple sclerosis or optic neuritis (category C, D, evidence398–407).
2010 Update:The demyelinating events tend to occur within the fi rst
5–8 months of use (category C evidence400 406).
Risks during pregnancyThe safety of anti-TNF therapy during pregnancy is unknown. Experts disagree about whether TNFα blocking agents should be stopped when pregnancy is being considered or whether they can be continued throughout pregnancy. Some studies found no increased fetal loss or miscarriages when using TNFα blockers, while one recent study found an increased rate of spontaneous abortions (category C, D evidence408–411).
A rare combination of congenital abnormalities (vertebral abnormalities, anal atresia, cardiac defect, tracheo-oesophageal, renal and limb abnormalities (VACTERL)) and partial VACTERL defect have been reported rarely, although the risk and causality are unclear (category C evidence410).
2010 Update (pregnancy)See general statement on page i2. According to the US
FDA, this drug class is considered category B, meaning no evidence of risk in humans. If no adequate human stud-ies are done, no animal studies have been done or animal studies show risk but human studies do not.
A systematic review of 667 pregnancies came to the conclusion that, to date, no defi nite harm to pregnancy can be ascribed to TNFα blocking agents (FDA category B evidence89).
A single patient study examined maternal serum, placenta, breast milk and infant etanercept levels, fi nding an approxi-mately 3% transfer of etanercept from serum to placenta
28. Schiff M, Keiserman M, Codding C, et al. Effi cacy and safety of abatacept or
infl iximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind,
placebo-controlled study in patients with rheumatoid arthritis and an inadequate
response to methotrexate. Ann Rheum Dis 2008;67:1096–103.
29. Genant HK, Peterfy CG, Westhovens R, et al. Abatacept inhibits progression of
structural damage in rheumatoid arthritis: results from the long-term extension of the
AIM trial. Ann Rheum Dis 2008;67:1084–9.
30. Wells G, Dougados M, Schmidely N, et al. Achievement of sustained low
disease activity state predicts the absence of structural damage progression in
patients with rheumatoid arthritis: insights from the abatacept database. J Rheum
2009;36:2593–4.
31. Haraoui P, Genant HK, Peterfy C, et al. Abatacept provides an increasing degree
of inhibition of structural damage progression through 3 years in patients with
the better since the introduction of biological agents into the
armamentarium of the treating physician. It is hoped that this
consensus statement will provide guidance to the clinician in
his/her efforts to improve the QoL of patients with these con-ditions. In addition, this consensus statement should provide evidence-based support for the selection of agents and justifi ca-tion for their use
APPENDICES: CATEGORIES OF EVIDENCECategory A evidence: based on evidence from at least one
randomised controlled trial or meta-analyses of randomised controlled trials. Also includes reviews if these contain cat-egory A references.
Category B evidence: based on evidence from at least one controlled trial without randomisation or at least one other type of experimental study, or on extrapolated recommen-dations from randomised controlled trials or meta-analyses.
Category C evidence: based on non-experimental descriptive studies such as comparative studies, correlational studies and case–control studies which are extrapolated from ran-domised controlled trials, non-randomised controlled stud-ies or other experimental studies.
Category D evidence: based on expert committee reports or opinions or clinical experience of respected authorities or both, or extrapolated recommendations from randomised controlled trials, meta-analyses, non-randomised controlled trials, experimental studies or non-experimental descriptive studies. Also includes all abstracts.
Author affi liations 1University of California at Los Angeles, Los Angeles, California, USA2University of Toronto, Toronto, Canada3Rheumazentrum Ruhrgebiet, Herne, Germany4Leiden University Medical Centre, Leiden, The Netherlands5Laboratorio di Reumatologia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy6Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, UK7University of Texas Southwestern Medical Center, Dallas, Texas, USA8Rheumatology/Medicine Hospital for Special Surgery, New York, New York, USA9University of Erlangen-Nuremberg, Erlangen, Germany10Rheumatology/Allergy Immunology, University of California, San Diego, San Diego, California, USA11Rheumatology Department/Guys Hospital, London, UK12Swedish Medical Center and University of Washington, Seattle, Washington, USA13Division of Rheumatology, MetroHealth Medical Center/Case Western Reserve
Society, Cleveland, Ohio, USA142nd Department of Medicine, Krankenhaus Lainz and Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria15Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands16Cedars Sinai Medical Center, Los Angeles, California, USA17Oregon Health and Science University, Portland, Oregon, USA
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1. Shekelle PG, Woolf SH, Eccles M, et al. Developing clinical guidelines. West J Med
1999;170:348–51.
2. Gladman DD, Helliwell P, Mease PJ, et al. Assessment of patients with
psoriatic arthritis: a review of currently available measures. Arthritis Rheum
2004;50:24–35.
3. Sokka T, Toloza S, Cutolo M, et al. Women, men and rheumatoid arthritis: analyses
of disease activity, disease characteristics and treatments in the QUEST-RA study.
Arthritis Res Ther 2009;11:R7.
4. Fransen J, Antoni C, Mease PJ, et al. Performance of response criteria for
assessing peripheral arthritis in patients with psoriatic arthritis: analysis of data from
randomised controlled trials of two tumour necrosis factor inhibitors. Ann Rheum Dis
2006;65:1373–8.
5. van der Heijde DM, Revicki DA, Gooch KL, et al. Physical function, disease activity
and health-related quality-of-life outcomes after 3 years of adalimumab treatment in
patients with ankylosing spondylitis. Arthritis Res Ther 2009;11:R124.
ANCA-associated vasculitisWG Keogh et al435 10: EffectiveWG/MPA Stasi et al436 10: 8WG/2MPA: EffectiveWG/MPA Eriksson et al437 9: 7WG/2MPA: EffectiveWG/MPA Keogh et al438 11: 10WG/1MPA: EffectiveWG/MPA/CSS Smith et al439 11: 5WG/5MPA/1CSS: EffectiveWG Aries et al440 8: Granulomatous manifestations: Effective
in 3; no response in 3; ineffective in 2WG Brihaye et al441 8: Refractory/relapsing: EffectiveWG Henes et al442 6: Refractory: EffectiveWG Golbin et al443 28: Refractory: EffectiveWG Sailler et al444 37: WG (3); autoimmune cytopenia19;
ANCA vasculitis Lovric et al445 15: Refractory ANCA-associated vasculitis: Effective
WG Seo et al446 8: EffectiveANCA associated Roccatello et al447 448 7: EffectiveWG Martinez et al449 34: EffectiveWG Guillevin et al450 21: As effective as infl iximabWG Ramos-Casals et al451 8: EffectiveWG Palm et al452 9: Effective: suppressing infl ammation not
airway stenosisRefractory WG Cohen et al453 22: As effective as infl iximabRefractory WG – meningitis Sharma et al454 1: EffectiveCSS Dønvik and Omdal455 2: EffectiveWG Martinez DelPero M et al456 34: EffectiveANCA vasculitis (children) Eleftheriou D et al457 17: EffectiveWG Taylor SR et al458 10: EffectiveANCA vasculitis Brito-Zeron et al459 19: Effective
Stone et al460 197: Effective (similar to Cytoxan)Hepatitis C-related vasculitis Terrier et al461 32: EffectiveCryoglobulinaemiaType II HCV-associated Sene et al462 6: IneffectiveType II and III Sansonno et al463 20: Effective
Continued
774. Sato H, Sakai T, Sugaya T, et al. Tocilizumab dramatically ameliorated life-threatening
diarrhea due to secondary amyloidosis associated with rheumatoid arthritis.
Clin Rheumatol 2009;28:1113–16.
775. Hirao M, Hashimoto J, Tsuboi H, et al. Laboratory and febrile features after joint surgery in
patients with rheumatoid arthritis treated with tocilizumab. Ann Rheum Dis 2009;68:654–7.
APPENDIX 1 ABATACEPTJIA-associated uveitis may improve with abatacept treat-ment (category C evidence427).
Table A1 Anecdotal studies using abataceptDisease Authors Patients (n) Outcome
Ankylosing spondylitis Olivieri et al428 1 PositiveBerner et al429 3 1 Positive
2 NegativeAutoimmune thrombocyotopenia Kloepfer et al430 1 PositiveGout Puszczewicz et al431 1 PositivePsA Mease et al432 1 PositiveSLE Merrill et al433 2 1 Negative
Type II Zaja et al464 15: 12 HCV: EffectiveType II HCV-associated Quartuccio et al465 5: EffectiveType III Basse et al466 7 : Renal transplant patients : 5 HCV:
EffectiveType II Bryce et al467 8: Essential 1; HCV/SS/LPD 7: Effective
Type II HCV-associated Saadoun et al468 16: EffectiveType II Cavallo et al469 13: EffectiveType II HCV-associated Ramos-Casals et al470 8: EffectiveType II HCV-associated Roccatello et al447 12: EffectiveType II HCV-associated Visentini et al471 6: EffectiveType II HCV-associated Roccatello et al472 6 HCV: 5 had GN: EffectiveType II Brito-Zeron et al459 9: EffectiveMixed Saadoun et al473 38: EffectiveHenoch–Schönlein purpura
Donnithorne et al474 3: EffectiveSjögren’s syndrome
Voulgarelis et al475 6: EffectiveDass et al476 17: Effective for fatiguePijpe et al477 15: 8 SS and 7 SS/MALT: EffectiveDevauchelle-Pensec et al478 16: SS: EffectiveSeror et al479 16: SS/NHL: EffectiveGottenberg et al480 6: 4 SS and 2 SS/MALT: Effective Galarza et al481 8: EffectiveMeijer et al482 8: SS/7 MALT: EffectiveSt Clair et al483 12: SS: EffectiveRamos-Casals et al451 10:EffectiveMeijer et al484 30: EffectiveVivino et al485 6: EffectiveRamos-Casals et al470 24: EffectiveTsirogianni et al486 11: EffectiveVasilyev et al487 11: EffectivePijpe et al488 5: EffectiveBrito-Zeron459 15: EffectiveGottenberg et al489 43: Effective
Juvenile idiopathic arthritisJuvenile autoimmune disease El-Hallak et al490 10: EffectiveJuvenile idiopathic arthritis Alexeeva et al491 50: EffectiveSystemic lupus erythematosusSLE Merrill et al433 257: IneffectiveRefractory SLE Tanaka et al492 15: Partially effectiveSLE haemolytic anaemia Gomard-Mennesson et al493 26:EffectivePaediatric SLE/LN Haddad et al494 11: EffectivePaediatric SLE MacDermott and Lehman495 ;
Marks and Tullus4967: Effective
Paediatric SLE/LN Marks and Tullus496 7:EffectiveSLE Ng et al497 7: Refractory: Effective 4/7Refractory SLE Tokunaga et al498 7: EffectiveSLE Leandro et al499 6: EffectiveSLE Leandro et al500 24: EffectiveSLE Looney et al501 17: EffectiveSLE Tokunga et al502 5: EffectiveSLE Ng et al503 41: EffectiveSLE Tanaka et al504 19: EffectiveSLE Amoura et al505 22: EffectiveSLE Welin-Henriksson et al506 20: EffectiveSLE Cambridge et al55 25: EffectiveSLE Gillis et al507 6: EffectiveSLE Nwobi et al508 18: EffectiveSLE Albert et al509 18: EffectiveSLE Boletis et al510 10: EffectiveSLE Jónsdóttir et al511 512 16: EffectiveSLE Lindholm et al513 31: EffectiveSLE: thrombocytopenia and haemolytic anaemia
Lindholm et al514 19: Effective
SLE Melander et al515 20: EffectiveSLE Reynolds et al516 11: EffectiveSLE Tanaka et al517 15: Effective
SLE Podolskaya et al518 19: EffectiveSLE Ramos-Casals et al451 27: EffectiveSLE Ramos-Casals et al451 27: EffectiveSLE Lu et al519 45: 19 achieved remission; 21 achieved
partial remission
Paediatric SLE with autoimmune thrombocytopenia and/or haemolytic anaemia
Kumar et al520 9: Effective
SLE Garcia-Carrasco et al521 52: EffectiveSLE Brito-Zeron459 107: EffectiveRefractory SLE Gilboe et al522 16: EffectiveSLE Terrier et al523 86: Effective
Karpouzas et al524 30: EffectiveRefractory SLE Garcia-Carrasco et al521 52: EffectiveSLE Karpouzas et al525 35: EffectiveSLE + Sjögren’s syndrome Logvinenko et al526 48: EffectiveLupus nephritisLN Guzman et al527 35: EffectiveLN Sangle et al528 16: Effective except in rapidly progressive
crescentic LNLN Sfi kakis et al529 7: EffectiveLN Jónsdóttir et al512 18: EffectiveRefractory LN Arce-Salinas et al530 8: EffectiveLN Pepper et al531 18: EffectiveLUNAR Furie et al532 144: IneffectiveRefractory juvenile-onset Olmos et al533 12: EffectiveLN Jónsdóttir et al534 58: EffectiveIdiopathic and infl ammatory myopathy/myositisDM Levine535 6: EffectiveDM Chung et al536 8: (partial response)PM Ramos-Casals et al451 3: EffectiveIdiopathic infl ammatory myopathy Sultan537 8: Effective in DM onlyDM Rios Fernandez et al538 4: EffectivePM Majmudar et al539 3: EffectivePM Frikha et al540 2: EffectiveDM Sánchez-Ramón et al541 1: Effective
Behçet diseaseRetinal vasculitis Sadreddini et al543 1: EffectiveSevere ocular lesions Davatchi et al544 10: EffectiveOcular infl ammatory disease Kurz et al545 4: EffectivePolyneuropathyIgM antibody associated polyneuropathy Pestronk et al546 21: EffectiveAnti-MAG antibodies associated with polyneuropathy
Renaud et al547 9: Effective
IgM antibody associated with polyneuropathy Levine et al548 5: EffectiveAnti-MAG antibodies associated with polyneuropathy
Benedetti et al549 13: Effective
Anti-MAG antibodies associated with polyneuropathy
Benedetti et al550 10: Effective
Anti-MAG antibodies associated with polyneuropathy
Dalakas et al551 13: Effective in 4
Demyelinating diseases of the CNSNeuromyelitis optica Cree et al552 8: EffectiveRelapsing-remitting MS Hauser et al553 69: EffectiveRelapsing-remitting MS Bar-Or et al554 26: EffectiveNeuromyelitis optica Genain et al555 9: EffectiveNeuromyelitis optica Jacob et al556 25: EffectiveMultiple sclerosis (primary progressive) Hawker et al557 439: IneffectivePemphigus, pemphigoid, epidermolysis bullosa and other dermatologicalBP, PV Schmidt et al558 7: EffectivePV Goh et al559 5: Partially effectivePV Cianchini et al560 12: EffectivePemphigus Joly et al561 21: EffectivePemphigus Marzano et al562 6: Effective
PV Allen et al563 42: EffectivePV Antonucci et al564 5: EffectiveAtopic eczema Simon et al565 6: EffectivePemphigus Shimanovich et al566 7: EffectivePemphigus (ocular) Foster et al567 12: Effective
Pemphigus Schmidt E et al568 136: EffectivePemphigus Pfütze M et al569 5: EffectiveSclerodermaScleroderma ILD McGonagle et al570 1: EffectiveScleroderma Lafyatis et al571 15: Not effectiveScleroderma skin Smith et al572 8: EffectiveScleroderma pulmonary/skin Daoussis et al573 14: EffectiveAntiphospholipid syndromeRelapsing catastrophic antiphospholipid syndrome
Asherson et al574 3: Effective
Relapsing catastrophic antiphospholipid syndrome
Manner et al575 1: Effective
Paediatric CAPS Nageswara Rao et al576 1: EffectiveBrito-Zeron459 5: Effective
Autoimmune pulmonary alveolar proteinosisBorie et al577 1: Effective
Relapsing polychondritisLeroux et al578 9: Ineffective
Mixed connective tissue diseaseAbdelghani et al579 5: Effective
Ankylosing spondylitisNocturne et al580 8: Ineffective
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i33
APPENDIX 4 TNFα BLOCKING AGENTS
Disease Author, ref no. Patients (n)
Tan et al583 1Consider intra-articular use of anakinra Birmingham et al598 7Cytophagic histiocytic panniculitis Behrens et al599 1Diabetes type 2 Larsen et al600 70
Larsen et al601 67Familial Mediterranean fever Bilginer et al602 1
Mitroulis et al603 1Moser C et al604 1Roldan R et al605 1Gattringer et al606 2Kuijk et al607 1Calligaris et al608 1Belkhir et al609 1
Gout So et al610 10Gratton et al611 1McGonagle585 1Singh et al612 1
GVHD Antin et al613 186Hyper-IgD syndrome Bodar et al614 3
Rigante et al615
Cailliez et al616 1Macrophage activation syndrome Kelly et al617 1Psoriatic arthritis Jung et al618 20
Gibbs et al619 12Recurrent pericarditis Picco et al620 3Relapsing polychondritis Vounotrypidis et al621 1
Wendling et al622 1Buonuomo et al623 1
Schnitzler’s syndrome Besada et al624 24Systemic lupus erythematosus Moosig et al625 3
Ostendorf et al626 4TNF receptor-associated periodic syndrome (TRAPS)
Morillas-Arques et al649 Adalimumab/etanerceptRozenbaum et al650 Anti-TNFSaulsbury and Mann651 Infl iximabSangle et al652 Infl iximab 1Sfi kakis et al653 Infl iximab 16Ribi et al654 Infl iximab 1Sweiss et al655 Infl iximab 3van Laar et al656 Adalimumab 6
Bronchiolitis Cortot et al657 Etanercept 1Cirrhosis and alcoholic hepatitis Naveau et al658 Infl iximab 36
Spahr et al659 Infl iximab 20Wendling et al342 Infl iximab 1Menon et al660 Etanercept 13
Cutaneous T-cell lymphoma Tsimberidou et al661 Etanercept 13Dermatitis, hidradenitis, miscellaneous Bongartz et al388 Infl iximab
Cortis et al662 EtanerceptCummins et al663 EtanerceptZeichner et al664 Adalimumab 1Cusack and Buckley665 Etanercept 6
Dermatomyositis Hengstman et al666 Infl iximab 2Miller et al667 Etanercept 10Sprott et al668 Etanercept 1Nzeusseu et al669 Infl iximab 1Saadeyh670 Etanercept 4Norman et al671 Etanercept 2
Erythema nodosum Ortego-Centeno et al672 Adalimumab 1Familial Mediterranean fever Takada et al673 Etanercept 2
Ozgocmen et al674 Etanercept 1Felty’s syndrome Ghavami et al675 Etanercept 1Giant cell arteritis Andonopoulos et al676 Infl iximab 2
Cantini et al677 Infl iximab 4Tan et al678 Etanercept 1Ahmed et al679 1
Graft vs host disease (acute) Wolff et al680 Etanercept 21Uberti et al681 Etanercept 20Kennedy et al682 Etanercept 20Chiang et al683 Etanercept 8Pavletic et al684 Etanercept 4Andolina et al685 Etanercept 1
Graves ophthalmopathy Paridaens et al686 Etanercept 10Hepatitis C Cacoub et al687 Interferon 27
McMinn et al688 Etanercept 3Peterson et al689 Infl iximab/etanercept 24Pritchard690 Etanercept 1Ince et al691 Etanercept 12Moreno et al692 Etanercept 5Allen and Wolverton563 Etanercept 2Marotte et al693 Etanercept 9Rokhsar et al694 Etanercept 1Magliocco and Gottlieb648 Etanercept 3
HIV immunodefi ciency (common variable) Wallis et al695 Etanercept 16Smith and Skelton696 Etanercept 1Lin et al697 Etanercept 1Cepeda et al698 Etanercept 7
Inclusion body myositis Barohn et al699 Etanercept 9 (ineffective)Singh et al700 Etanercept 1
Juvenile-onset HLA-B27-associated severe and refractory heal enthesitis
Olivieri et al701 Adalimumab 1
Kawasaki’s disease Weiss et al702 Infl iximab 1Burns et al703 Infl iximab 16
Multicentric histiocytosis Lovelace et al704 Etanercept 1Matejicka et al705 Etanercept 1Kovach et al706 Etanercept 1
Myelodysplasia Birnbaum and Gentile707 Etanercept 1Deeg et al708 Etanercept 14Rosenfeld and Bedell709 Etanercept 19 (ineffective)Raza et al710 Etanercept 26
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852 i35
Disease Author, ref no. Drugs Patients (n)
Maciejewski et al711 Etanercept 16Osteoarthritis (erosive) Magnano et al712 Adalimumab 12Periodic fever (children) Athreya et al713 Etanercept 3Pigmented villonodular synovitis Kroot et al714 TNF blocking agent Polychondritis Carter716 Infl iximab 1
Ehresman717 Etanercept 5Polymyositis Hengstman et al666 Infl iximab 2
Sprott et al668 Etanercept 1Adams et al715 Adalimumab 2
Pyoderma gangrenosum Fonder et al718 Adalimumab 1Sacroiliitis ankylosing spondylitis Heffernan et al719 Adalimumab 1SAPHO syndrome Anker and Coats720 lnfl iximab/etanercept 150
Sweiss et al721 Infl iximab 3Callejas-Rubio et al722 Adalimumab 1Korhonen et al723 Infl iximab 12Korhonen et al724 Infl iximab 40Lam et al725 Infl iximab 18Pasternack et al726 Etanercept 4Tobinick and Davoodifar727 Etanercept 43Khanna et al728 Etanercept 1Utz et al729 Etanercept 17Wagner et al730 Etanercept 2Moul and Korman731 Adalimumab 1
Sarcoidosis Khanna et al728 Etanercept 1Utz et al729 Etanercept 1Heffernan and Smith732 Adalimumab 1Callejas-Rubio722 Adalimumab 1Querfeld733 Etanercept 1Sweiss et al655 Etanercept 1Hobbs734 Etanercept 1
Scleroderma Ellman et al735 Etanercept 8Bosello et al736 Etanercept
Silicone granulomas Pasternack et al726 Etanercept 4Sjögren’s syndrome Zandbelt et al737 Etanercept 15 (ineffective)
Sankar et al738 Etanercept 14(ineffective)Pessler et al739 Etanercept 1
Still’s disease (includes adult onset) Fautrel et al740 Etanercept 20 (ineffective)Stern et al741 Etanercept 1 (worsening)Asherson et al742 Etanercept 1Kumari and Uppal743 Etanercept 1
Sweet’s syndrome Gindi et al744 Etanercept 1Yamauchi et al745 Etanercept 24
Systemic lupus erythematosus Aringer et al746 Infl iximab 6Fautrel et al740 Etanercept 1 (SCLE)Lurati et al747 Etanercept 1Norman et al671 Etanercept 1 (SCLE)Hernandez-Ibarra et al748 N/A –Principi et al749 Infl iximab 1
Takayasu’s arteritis Hoffman et al750 Anti-TNF 15Della Rossa et al751 Infl iximab 2Tato et al752 Adalimumab 1
TRAPS Hull et al753 Etanercept >50Lamprecht et al754 Etanercept 2Drewe et al755 Etanercept 1Estrach et al644 Infl iximab/adalimumab 7Joseph et al756 Infl iximab 5Smith et al757 Etanercept 7Braun et al758 Etanercept/infl iximab 717(uveitis in AS)Foster et al759 Etanercept 20 (ineffective)Biester et al760 Adalimumab 18Foeldvari et al286 Anti-TNF 47Vazquez-Cobian et al761 Adalimumab 14Reiff et al762 Etanercept 10Schmeling and Horneff763 Etanercept 20 (ineffective)Guignard et al764 Adalimumab 8
Ann Rheum Dis 2011;70(Suppl 1):i2–i36. doi:10.1136/ard.2010.146852i36
Disease Author, ref no. Drugs Patients (n)
Vasculitis* Booth et al765 Infl iximab 32Feinstein and Arroyo766 Etanercept 1van der Bijl et al767 Infl iximab 11Saji and Kemmotsu768 Infl iximab 1 (Kawasaki’s
disease)Sangle et al652 Infl iximab 1 (Churg–Strauss)Arbach et al769 Etanercept/infl iximab 3
Wegener’s granulomatosis Gause et al770 Infl iximab 10 Sangle et al652 Infl iximab 3
Table A5Disease Authors Patients (n) Outcome
Reactive arthritis Tanaka et al772 1 PositiveAmyloidosis Nishida et al773 1 Positive
Sato et al774 1 PositiveAfter joint surgery Hirao et al775 ?
Table A4 Continued
APPENDIX 5 ANECDOTAL STUDIES USING TOCILIZUMABTocilizumab to include iritis (JIA) in a dose of 8 mg/kg every 2 weeks (category A evidence134) and in polyarticular JIA (cat-egory A, D evidence132).