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Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2009
  1. D E Furst1,
  2. E C Keystone2,
  3. R Fleischmann3,
  4. P Mease4,
  5. F C Breedveld5,
  6. J S Smolen6,
  7. J R Kalden7,
  8. J Braun8,
  9. B Bresnihan9,
  10. G R Burmester10,
  11. F De Benedetti11,
  12. T Dörner12,
  13. P Emery13,
  14. A Gibofsky14,
  15. A Kavanaugh15,
  16. B Kirkham16,
  17. M H Schiff17,
  18. J Sieper18,
  19. N Singer19,
  20. P L C M Van Riel20,
  21. M E Weinblatt21,
  22. M H Weisman22,
  23. K Winthrop23
  1. 1
    University of California at Los Angeles, Los Angeles, USA
  2. 2
    University of Toronto, Toronto, Canada
  3. 3
    University of Texas Southwestern Medical Center, Texas, USA
  4. 4
    Seattle Rheumatology Associate, Seattle, USA
  5. 5
    Leiden University Medical Centre, Leiden, The Netherlands
  6. 6
    2nd Department of Medicine, Krankenhaus Lainz, and Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria
  7. 7
    University Erlangen-Nuremberg, Erlangen, Germany
  8. 8
    Rheumazentrum Ruhrgebiet, Germany
  9. 9
    Rheumatology Department, St Vincents Hospital, Dublin, Ireland
  10. 10
    Department of Rheumatology, Charite-University Medicine, Berlin, Germany
  11. 11
    Laboratorio di Reumatologia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
  12. 12
    Institut für Transfusionsmedizin, Klinische Hämostaseologie, Charite Universitätsmedizin Berlin, Berlin, Germany
  13. 13
    Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, UK
  14. 14
    Rheumatology/Medicine Hospital for Special Surgery, New York, New York, USA
  15. 15
    University California San Diego, Rheumatology/Allergy Immunology, La Jolla, California
  16. 16
    Rheumatology Department/Guys Hospital, London, UK
  17. 17
    University of Colorado, Denver, Colorado, USA
  18. 18
    Department of Medicine/Rheumatology, Charite Campus Benjamin Franklin, Berlin, Germany
  19. 19
    Division of Pediatric Infectious Disease and Rheumatology Division of Rheumatic Diseases, Department of Medicine Rainbow, Babies and Children’s Hospital, Cleveland, Ohio, USA
  20. 20
    University Hospital Nijmegen, Nijmegen, The Netherlands
  21. 21
    Brigham and Womens Hospital, Boston, Massachusetts, USA
  22. 22
    Cedars Sinai Medical Center, Los Angeles, California, USA
  23. 23
    Oregon Health and Science University, Oregon, USA
  1. Correspondence to Professor D E Furst, David Geffen School of Medicine, UCLA – RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA; defurst{at}mednet.ucla.edu

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As in previous years, the consensus group to consider the use of biological agents in the treatment of rheumatic diseases met during the 11th Annual Workshop on Advances in Targeted Therapies. The group consisted of rheumatologists from a number of universities among the continents 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 conference. Representatives of the supporting sponsors 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 perspective of the treating physician.

In view of the new data for abatacept,1 B-cell-specific agents,2 interleukin 1 receptor antagonists (IL1ra),3 tocilizumab (TCZ),4 and tumour necrosis factor α (TNFα) blocking agents,5 an update of the previous consensus statement is appropriate. The consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in the appendix.6 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 abatacept1 and rituximab (B-cell specific therapy),2 as well as IL1 blocking agents,3 TCZ4 and TNF 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, representing 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 FDA or EMEA (European Medicines Agency) for clinical use. Extensive tables of the use of these agents in non-registered uses are included as appendices, to help experienced doctors to use these drugs in exceptional (“off-label”) circumstances.

General statements

Individual patients differ in the clinical expression and aggressiveness of their disease, its concomitant structural damage, the effect of their disease on their quality of life (QoL) and the symptoms 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 examined 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 ankylosing spondylitis (AS), these diseases will be discussed 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 time, the American College of Rheumatology (ACR) response criteria (as a combined index) should not be used in a clinical practice setting to monitor individual response, although some validated measure of response (such as those which follow) should be employed (category B evidence2 7). Validated quantitative measures such as the Disease Activity Score (DAS), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), 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 of pain 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. 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, global and pain response measures, functional indices and acute phase reactants have been used.1 2 3 For AS, measures such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Bath Ankylosing Spondylitis Functional Index (BASFI) have been used in clinical trials but have not been validated for routine clinical practice (category C evidence8). 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.

The appropriate use of biological agents will require doctors experienced in the diagnosis, treatment and assessment of RA, PsA, AS and other rheumatic diseases who are aware of long-term observations of efficacy and toxicity, including cohort studies and data from registries. Because biological agents have adverse effects, patients or their representatives should be provided with information about potential risks and benefits so that they may give informed consent for treatment.

Abatacept

One agent which modulates T-cell activation (abatacept) has been approved in the United States and Europe.

Indications

Rheumatoid arthritis

Abatacept is approved in North America for use alone or with background DMARDs for treatment of moderate to severe adult RA or polyarticular JIA.

Abatacept is recommended for treatment of active RA as monotherapy or with DMARDs after an adequate trial of methotrexate (MTX) or another effective DMARD (in the USA). Abatacept has been approved by the EMEA for active RA after an inadequate response to a non-biological DMARD and includes 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 (category C evidence9). Abatacept has been used with MTX and other DMARDs (category A evidence10 11 12 13 14 15).

Clinical use

Dosing and time to response

Abatacept is administered as intravenous infusions of approximately 8 or 10 mg/kg (500 mg for weights less than 60 kg; 750 mg for weights of 60–100 kg and 1000 mg for weights over 100 kg) at 0, 2, 4 weeks and then monthly (FDA product label).

Abatacept decreases signs and symptoms of RA and improves physical function in adult patients with moderately to severely active RA who have had an inadequate response to one or more DMARDs such as MTX or TNF blocking agents (category A evidence10 11 16 17).

2009 Update:

In MTX-naïve patients with early RA, MTX plus abatacept was better than MTX plus placebo (category B evidence18).

Some patients respond to abatacept, according to the ACR response criteria, within 2–4 weeks. Most patients respond within 12–16 weeks of starting treatment. Patients continue to improve for up to 12 months (category A evidence19 20 21). Quality of life and other patient-related outcomes such as sleep, fatigue and activity also improve (category A evidence22 23 24 25 26 27).

Persistence and degree of response

Some patients continue to respond to 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 evidence12 14).

Comparison with TNFα blocking agents

The efficacy of abatacept was similar to infliximab at 3 mg/kg with numerically fewer serious adverse events in the abatacept-treated patients (category A evidence28).

Structural changes

Abatacept in combination with MTX slows radiographic progression in RA in MTX-IR (category A, B, C evidence14 25 29 30 31).

Safety

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.

Autoimmune disease

2009 Update:

No increased incidence of autoimmune diseases was noted in the abatacept clinical trial database (category D evidence32).

Infections

Tuberculosis

All patients in abatacept phase 3 trials were screened for tuberculosis (TB) with a tuberculin skin test but were still included if the screen was positive and they were treated for latent TB. There are cases of TB observed in the clinical trial programme (category C, D evidence33 34). 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 treatment for TB according to local practice.

Serious infections

In comparison with placebo in clinical trials the incidence of serious infections with abatacept was increased in one trial but not in a meta-analysis (category A evidence34 35). In a review of clinical trial data, the incidence of hospitalisations for infections remained stable for up to 3 years and the incidence did not differ in the long-term extension as compared with the blinded phase of clinical trials. As with the other such trials, the uncontrolled cohort design with observed data limits the generalisability of these data (category C evidence34).

In combination with other biological agents, the rate of serious infections is 4.4% (vs 1.5% in controls; category C evidence15) The use of abatacept with TNF blocking agents is not recommended, as an increased incidence of serious infections was noted when the combination was used (category A evidence36 37). There are no data about the combination of abatacept and rituximab.

2009 Update:

There was a decreased response to influenza, tetanus and pneumococcal vaccinations when using abatacept in healthy volunteers (category C evidence38). Influenza and pneumococcal vaccinations in patients with RA receiving abatacept were reduced as in previous reports of patients with RA receiving MTX (category D evidence39).

Owing to theoretical concerns, live vaccines should not be given while a patient is receiving abatacept or within 3 months of using abatacept.

Malignancies

There has been one case of a lymphoma occurring 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 evidence40 41). While this number is consistent with that expected from large RA cohorts, continuing surveillance is necessary.

2009 Update:

In a comparison of abatacept clinical trial data with national registries, no increased rates of lymphoma, lung, breast, colorectal or total malignancies were found, although the control populations were not completely comparable (category D evidence40). Epidemiological experience in six RA cohorts shows no increased rate of solid malignancies compared with the RA cohorts (category D evidence41), but continued monitoring is necessary.

Summary

Abatacept is effective for the treatment of moderate to severe RA in patients who have had an inadequate response to MTX or to at least one TNFα blocking agent. The safety of abatacept is still being defined, although caution is advised when using abatacept in the presence of COPD.

Rituximab (RTX) B-cell therapy

Rituximab 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. More than 1 000 000 patient exposures (usually four infusions per patient) have been documented over 9 years in postmarketing surveillance of these patients with NHL. A consensus statement on the use of rituximab in patients with RA has been published (category D evidence42).

Indications

Rheumatoid arthritis

Rituximab has been approved by the FDA in the USA for the treatment of moderate-to-severe RA with MTX in patients who have had an inadequate response to at least one TNFα blocking agent (category A, D evidence43 44 45) (FDA and EMEA label; category C, D evidence46 47 48 49 50 51). It may also be used when TNF inhibitors are not suitable (category D evidence52 53 54).

Current evidence on the efficacy of rituximab relates to rheumatoid factor-positive patients (category C evidence46 48). More robust ACR responses were seen with rituximab in rheumatoid factor/anti-CCP-positive patients, in DMARD non-responders (category C evidence46 48) and in TNF non-responders (category D evidence46 52 55 56).

Clinical use

Dosing and time to response

Rituximab is administered intravenously as two 1 g or two 500 mg (MTX-IR patients) rituximab infusions (given with 100 mg methylprednisolone or equivalent) separated by an interval of 2 weeks (category A evidence46 47 48 49 50 51 57 58). In RA, it may be used alone or in combination with MTX (category A and D evidence43 44 45 54 55 58). The optimal treatment schedule is currently under investigation (category D evidence43 46 48 52 55).

In clinical trials, rituximab results in significant improvement in signs and symptoms and/or laboratory measures by 8–16 weeks (category A, D evidence58 59 60 61 62 63 64 65).

Persistence and degree of response

Rituximab is effective in patients with an inadequate response to MTX for whom conventional DMARDS have failed or who have used one or more TNF inhibitors (category A, B evidence57 58 64 65 66 67). Improvement has also been demonstrated in patient-related outcomes such as HAQ-DI, patient global VAS, fatigue, disability and QoL (category A, evidence68 69). Evidence from randomised controlled trials shows that the combination of rituximab with MTX yields better clinical efficacy for RA than monotherapy (category A evidence44 48 53 70).

Studies have shown that repeated treatment courses are effective in previously responsive patients with RA (category C, D evidence63 66 71). Most of the patients who received subsequent courses did so 24 weeks or more after the previous course and none received repeated courses earlier than 16 weeks after the previous course (category D evidence71). There are conflicting data on the efficacy of retreatment of initial non-responders (category C evidence73).

2009 Update:

In a retrospective non-randomised open-label study, patients for whom one or more TNF antagonists had been ineffective were switched to RTX and this drug was more effective than using another TNF inhibitor.74

Repeat dosing studies revealed that in MTX-IR patients, escalation from 500 mg per infusion to 1000 mg in the second course was equivalent to two courses of 500 mg or 1000 mg (unpublished data) but in TNF-IR patients two courses of 1000 mg ×2 appear to be more efficacious than two courses of 500 mg ×2 (category C evidence75).

Open-label extension studies of up to 6 years showed continued response (category D evidence76). DMARDs other than methotrexate can be used with rituximab (category D, evidence73).

Structural changes

There are data indicating that rituximab can slow radiographic progression in patients who have had an inadequate response to one or more TNF blockers (category A evidence77).

2009 Update:

Radiographic progression is slowed for up to 2 years within clinical trials (category A evidence78).

Safety

Hepatitis

2009 Update:

Hepatitis B status should be assessed before treatment. Rituximab treatment is normally contraindicated in hepatitis B since fatal hepatitis B reactivation has been reported in patients with NHL treated with rituximab.

RTX has been used in HCV associated cryoglubulinaemic vasculitis (category A, D evidence79 80).

Infections

Tuberculosis

In 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 TNF inhibitor non-responders, patients with active TB were excluded. Others were screened by chest x-ray examination, but were not screened for latent TB by purified protein derivative testing. There is no evidence of an increased incidence of TB in patients with NHL treated with rituximab. There are insufficient 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 opportunistic infections.

Severe infections

Similar to the TNFα blocking agents and the other biological agents, a small increase in serious infections (not intracellular infections) in patients receiving rituximab 2×l000 mg compared with placebo has been reported (category A evidence81).

2009 Update:

There is no increase in the incidence of serious infectious events with increasing numbers of rituximab courses (up to five courses; category A, D evidence48 76 82).

No increase in the rate of serious infections was seen in a cohort of 185 patients who received another biologic after rituximab treatment compared with patients receiving RTX treatment before a biological agent (category D evidence83).

Since baseline immunoglobulin levels were generally normal in patients entering clinical studies, and decreased levels of immunoglobulin M, A and G have been seen with rituximab, it may be useful to determine baseline immunoglobulin levels (category D evidence44 49 54 55 66). In clinical trials 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 evidence49 55).

2009 Update:

After repeat courses of RTX, a proportion of patients develop IgG levels below the lower limit of normal. The significance of these immunoglobulin decreases is unclear and further studies are required (category C, evidence76 82).

B-cell levels have been measured in clinical trials but their importance in routine practice has not been proved. More complete depletion of peripheral levels of the CD20+ B-cell subpopulation was inconsistently predictive of achieving or maintaining a clinical response in patients with RA (category D evidence50 84 85 86 87 88). This suggests that the timing of re-treatment should be based on disease activity rather than repletion of peripheral B-cell levels.

Vaccination

Since rituximab causes B-cell depletion, it is recommended that any vaccinations required by the patient, such as those to prevent pneumonia and influenza, should be given before starting treatment. While receiving treatment, appropriate vaccination (such as against influenza) should be given when indicated, although the responses have been shown to be submaximal (category A evidence89).

2009 Update:

In a controlled trial, rituximab significantly decreased the immune response to neoantigen, (KLH), and pneumococcus, whereas DTH responses and responses to tetanus were unchanged (category A evidence90).

Until further data are available, the use of live attenuated vaccines should only be given before the use of rituximab.

Infusion reactions

The most widespread adverse events are infusion reactions, which are most common with the first infusion of each course (up to 35%) and are reduced with the second and subsequent infusion (about 10%). Intravenous corticosteroids were shown to reduce the incidence and severity of infusion reactions by about 30% without changing efficacy (category A, C and D evidence43 44 46 48 52 53 54 55 57). Rare anaphylactoid reactions have occurred when rituximab is used (category C evidence91).

Malignancies

There is no evidence that rituximab is associated with an increased incidence of solid tumours in RA. Nevertheless, vigilance for the occurrence of solid malignancies remains warranted during treatment with rituximab (category B evidence76).

Neurological syndromes

Cases of progressive multifocal leucoencephalopathy (PML) have been seen in patients with systemic rheumatic diseases with and without rituximab treatment (FDA communication). Two cases of PML in patients with RA treated with rituximab have been reported. The causal relationship between PML and rituximab remains unclear.

Skin reactions

Rare reports of psoriasis, including severe cases, have been reported in patients with RA, SLE and NHL after rituximab treatment (category D evidence92 93). The causative role of rituximab in this circumstance remains unknown.

Summary

Rituximab is effective in patients with an inadequate response to MTX for whom conventional DMARDS have failed or who have used one or more TNFα blocking agents. The safety of rituximab is still being defined. It is hoped that this statement, based on the best evidence available at this time, and modified by expert opinion, will facilitate the optimal use of these agents.

IL1 blocking agents

One IL1 blocking agent, anakinra (IL1ra), has been approved for use in RA. A second IL1 inhibitor, rilonacept (IL1 Trap), has recently been approved for use in cryopyrin-associated periodic syndromes (CAPS; category A, C evidence94 95 96).

Indications

Rheumatoid arthritis

Anakinra may be used for the treatment of active RA, alone or in combination with MTX, at a dose of 100 mg/day subcutaneously (category A evidence96 97 98 99 100 101). In Europe, the anakinra label requires prescription in combination with MTX. Anakinra is recommended for the treatment of active RA after an adequate trial of non-biological DMARDs or with other DMARDs (category A evidence98 99; category C evidence102). No trials of anakinra as the first DMARD prescribed for patients with early RA have been published.

Juvenile idiopathic arthritis (JIA) and adult-onset Still’s disease

Anakinra is effective in a proportion of patients with systemic-onset JIA and adult-onset Still’s disease (category D evidence103 104).

2009 Update:

Cryopyrin-associated periodic syndromes

Anakinra and rilonacept have clinical benefits in relatively small numbers of patients with CAPS, including familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal-onset multisystem inflammatory disease, which are characterised by mutations in the NALP3 gene (category A, C evidence95 102 104). Successful treatment with anakinra in children with idiopathic recurrent pericarditis suggested that this disorder may be a previously unrecognised autoinflammatory syndrome (category D evidence105).A placebo-controlled randomised clinical trial has highlighted the clinical efficacy of rilonacept in patients with CAPS7 (category A evidence95).

Clinical use

Timing of response

Anakinra can lead to significant improvement in symptoms, signs and/or laboratory parameters of RA within 16 weeks, and can slow the rate of radiographic progression (category A evidence96 97 98 100). If improvement is not seen by 16 weeks, the continued use of anakinra should be reconsidered.

Comparison with TNFα blocking agents

Despite the lack of head-to-head comparisons, anakinra is considered to be less effective than TNF blocking agents (category B evidence106). Clinical trials of patients for whom anti-TNF therapy has failed showed variable responses to anakinra (category C evidence101).

Infections

Tuberculosis

To date, there is no indication that use of anakinra is associated with an increased incidence of TB (category D evidence107).

Bacterial infections

The frequency of serious bacterial infections was increased in patients receiving anakinra, and its incidence is higher than in patients with RA using non-biological DMARDs. The increased incidence of infection was greatest in patients who were also receiving corticosteroids (category A evidence99; category C evidence107). Patients should not start or continue anakinra if a serious infection is present (category A evidence4 109 110 111; category C evidence107; category D evidence112). Treatment with anakinra in such patients should only be resumed if the infection has been adequately treated.

When anakinra was used in combination with etanercept, there was no increase in efficacy. However, an increase in the incidence of serious infection was seen in comparison with either compound used as monotherapy. Therefore, the combination of anakinra and etanercept should not be prescribed (category A evidence113).

Vaccinations

2009 Update:

In one controlled trial, anakinra did not inhibit anti-tetanus antibody response (category D evidence114).

Injection site reactions

A dose-related incidence of injection site reactions, affecting up to 70% of patients, has been reported with the use of anakinra. These reactions often do not require treatment and seem to moderate with continued use in most patients (category A evidence96 97 98).

Summary

Anakinra and rilonacept are effective in the treatment of CAPS. It is also effective in the treatment of JIA, adult Still’s disease and RA, but its position in the therapeutic algorithm of RA is unclear.

Ankylosing spondylitis and psoriatic arthritis

Anakinra has been evaluated in two open-label studies of AS, but without consistent evidence of efficacy.115 116 Anakinra did not demonstrate clinical efficacy in PsA.43

Crystal-associated arthropathies

There are anecdotal reports of clinical efficacy after treatment with anakinra in patients with intractable gout116a and pseudogout116b.

Other arthropathies

Treatment with intra-articular anakinra was evaluated in a randomised clinical trial of patients with osteoarthritis.117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 Treatment was well tolerated but no improvements were seen compared with placebo. There are anecdotal reports concerning the use of anakinra in patients with systemic lupus erythematosus, Behçet disease and relapsing polychondritis.

Tocilizumab

Tocilizumab is a humanised anti-IL6 receptor monoclonal antibody (category A/D evidence137 138 139 140 141 142).

Indications

Tocilizumab has been approved in the European Union and a number of other countries in combination with MTX or as monotherapy for the treatment of moderate-to-severe active RA in adults who are incomplete responders (owing to adverse effects or lack of response) to DMARDs or TNF blocking agents (category A, D evidence137 138 139 140 141 142 144).

In Japan and India tocilizumab has also been approved for polyarticular JIA, systemic-onset JIA and multicentric Castleman’s disease (category A, D evidence145 146 147 148).

Clinical use

Tocilizumab reduces signs and symptoms of active RA in incomplete responders to DMARDs or TNF blocking agents (category A, D evidence137). Tocilizumab can be used as monotherapy in DMARD/MTX-naïve patients (category A, D evidence141) or DMARD inadequate responders (category A, D137 138 139 140 142).

Dosing

Tocilizumab is administered intravenously monthly in a dose of 4 or 8 mg/kg (category A, D137 138 139 140 141 142 142). 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, D evidence137 138 139 140 142).

Timing of response

Onset of response occurs between 2–4 weeks in some patients but it may evolve for up to 24 weeks. (category A, D evidence2).

Juvenile idiopathic arthritis

Tocilizumab improves systemic signs and symptoms in patients with systemic-onset JIA in a dose of 8 mg/kg every 2 weeks (category A evidence147) and in polyarticular JIA (category A, D evidence144).

Comparison with TNF blocking agents

Tocilizumab has not been compared directly with TNF blocking agents. It can be used after failure of one or more TNF blocking agents (category A evidence149).

Structural changes

Tocilizumab inhibits radiographic progression in patients who have had an inadequate response to MTX or other DMARDs (category A, D evidence140 142), and it slows radiographic progression as monotherapy (category A evidence144).

Safety

Cardiovascular end points and lipid levels

The overall long-term effect of TCZ on cardiovascular outcomes is at present not known. Increases in mean fasting plasma lipid levels were seen in TCZ-treated patients relative to controls, including total cholesterol, low-density lipoprotein and triglycerides with smaller increases in high-density lipoprotein (category A, D evidence150 151 152 153).

2009 Update:

Initiation of statin therapy after receiving TCZ is effective in reducing lipids (category D evidence154). In follow-up for a median of 1.5–5 years (category D evidence146 152), there was no apparent increase in cardiovascular event rates. Hypertension and cerebrovascular accidents have been seen (category A, D evidence137 138 139 140 141 142 149 150 151 142 149152). In follow-up with a median of 1.5 years, there is no increase in the rate of cerebrovascular accidents (category D evidence140).

Gastrointestinal

2009 Update:

During 6-month controlled trials, generalised peritonitis, lower gastrointestinal perforation, fistulae and intra-abdominal abscesses have been reported. Tocilizumab should be used with caution in patients with a history of intestinal ulceration or diverticulitis (category A, D evidence140).

Haematological

Neutropenia: A higher proportion of patients treated with TCZ had a decrease in the absolute neutrophil count compared with placebo.

2009 Update:

A few patients had a decrease of polymorphonuclear cells to <1000 and/or 500 cells/mm3. This change usually occurs early after a dose and is transient. Complete blood counts should be monitored regularly. In one study, there was an accompanying increase in infections but this was not seen in most studies (category A, D evidence155 156).

Increases in hepatic aminotranferase and bilirubin

Increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred with similar frequency with TCZ monotherapy compared with MTX alone (category A evidence157 158 159). In combination with MTX, increases are more common.

2009 Update:

Increases of bilirubin, mostly indirect, occur separately and are not associated with hepatic dysfunction. Liver function should be monitored regularly. Guidelines consistent with those for MTX for the management of TCZ-related laboratory abnormalities have been included in the EMEA package.144 No instances of TCZ-induced hepatic failure or liver damage have been documented (category A, D evidence137 138 139 140 141 142 156 142 156 158).

Infections

Bacterial Infections

The incidence of serious infection at rates up to 4.6/100 patient-years was stable in a median follow-up of 1.5 years (category D evidence152). TCZ should not be given in the presence of serious or opportunistic infections (category D evidence140). As with other biological agents careful observation for bacterial infections is necessary (category A, D evidence134 135 136 137 138 139 140 141 142 152 154 155).

Tuberculosis and opportunistic infections

Patients with active tuberculosis and atypical mycobacterial infections were excluded in all studies, so there are insufficient data provide information about the need for TB screening before initiating TCZ treatment. Local practice for TB screening should be observed. Cases of TB have been seen in patients taking TCZ (EMEA; category D evidence140).

Viral infections

Cases of localised H zoster infection have occurred in clinical trials, but it is not clear whether H zoster is increased in association with TCZ (category D evidence139 140).

Vaccination

Safety and response to vaccinations were evaluated in patients with RA receiving TCZ. Most patients could be effectively immunised with influenza vaccine (category D evidence157). As for the other biological agents, live vaccines should not be given while patients are receiving TCZ (category A, D evidence140 156 157).

Infusion-related events

Serious infusion reactions during/after treatment with TCZ are uncommon (category A, D160).

Malignancies

There is no evidence that TCZ treatment is associated with an increased incidence of malignancies in patients with RA (category A, D evidence137 138 139 140 141 142 144 145 146 148 150). Systematic safety surveillance should be performed during TCZ treatment, similar to requirements for other biological agents.

Summary

Tocilizumab is effective in patients with an inadequate response to MTX for whom conventional DMARDs have failed or who have had one or more TNFα inhibitors. It is also effective as monotherapy and in one study was better than MTX. The safety of TCZ requires further evaluation in long-term extension studies and surveillance databases.

Research agenda

  • Studies are needed to determine whether immunisation with vaccinations should be carried out in adults before initiation of TCZ.

  • Studies are needed with respect to the incidence of TB and opportunistic infections when using TCZ.

  • Continued follow-up is necessary to ascertain relationships between TCZ and cardiovascular events, hepatic failure, viral illness (including H zoster) and malignancy.

TNF blocking agents

TNF blocking agents 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 discussed, where appropriate.

Indications

Rheumatoid arthritis

In most patients, TNFα blockers are used in conjunction with another DMARD, usually MTX. TNFα blocking agents have also been used successfully with other DMARDs, including sulfasalazine and leflunomide. They are effective for the treatment of RA in MTX-naive patients (category A evidence109 112 115 116 161 162 163 164 165 166 167; category D evidence168). TNFα blocking agents can be used as the first DMARD in some patients (category A evidence110; category D evidence34 109 163 167). Adalimumab and etanercept are both approved as monotherapy for RA. Infliximab is only approved for use with MTX in RA. However, observational data indicate that infliximab, too, is sometimes used as monotherapy (category C evidence169 170 171). The combination of a TNFα blocking agent and MTX yields better results for RA than monotherapy, particularly with respect to excellent clinical responses (ACR 70, remission) and radiological outcomes (category A evidence172 173 174).

2009 Update:

Comparison of MTX + TNF blockers and combinations of traditional DMARDs plus steroids have been made for up to 2 years. Preliminary data indicate that combinations of traditional DMARDs, while effective in some patients, are less effective on a group level than combinations of MTX plus infliximab, MTX plus etanercept or MTX plus adalimumab (category A evidence175).

Psoriatic arthritis

Based on the demonstration of control of signs and symptoms of joint and skin disease, improvement of function, QoL and inhibition of structural damage, the available TNFα blocking agents (adalimumab, etanercept, golimumab and infliximab) have been widely approved for the treatment of patients with PsA for whom conventional treatments have produced an inadequate response. Efficacy has been demonstrated both with monotherapy and with background MTX (category A evidence75 176 177 178 179 180 181 182 183 184 185 186).

Ankylosing spondylitis

Adalimumab, etanercept, golimumab and infliximab have been widely approved for the treatment of active AS that is refractory to conventional treatments. In clinical trials, the efficacy 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 evidence187 187 189 190 191 192 193; category D evidence192). There is no evidence that combination therapy with conventional DMARDs is better than monotherapy with TNF blocking agents.

Juvenile idiopathic arthritis

Etanercept and adalimumab have been approved for JIA with a polyarticular course (FDA: ⩾2 years for etanercept: ⩾4 years for adalimumab; EMEA: age 13–17 years for both) (category A evidence111 194 195 196; FDA and EMEA approvals). Infliximab was beneficial at 6 mg/kg in polyarticular JIA (category A evidence194 195).

Appendix 3 provides evidence supporting the use of TNFα blocking agents in other rheumatic diseases or those with prominent rheumatic manifestations.

Clinical use

Rheumatoid arthritis

Dosing and time to response

Increasing the dose or reducing the dosing intervals of infliximab and adalimumab may provide additional benefit in RA, whereas increased doses of etanercept have increased benefit on a group level (category A evidence197 198). The addition or substitution of other DMARDs may increase efficacy in some patients.

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 significant, documentable improvement in symptoms, signs and/or laboratory parameters within 12–24 weeks (category A, B evidence117 199 200 201 202 203 204 205 206). Clinically significant important responses including patient-oriented measures (eg, HAQ-DI, patient’s global VAS, Medical Outcome Survey Short Form 36 (SF-36)) and physical measures (eg, joint counts)) should be demonstrated within 12–24 weeks for RA (category A evidence4 5 34 109 112 115 116 161 162 163 164 165 166 167 170 171 173 199 204 205). If such improvement occurs, treatment should be continued. If patients show no response to these agents, their continued use should be re-evaluated.

2009 Update:

For remission or low disease activity, anecdotal studies indicate that lowering the dose may be successful without loss of effect (category C evidence207).

Comparing TNFα blocking agents

There is no evidence that any one TNFα blocking agent should be used before another one can be tried. There is also no evidence that any TNF blocking agent is more effective than any other in RA (category A and B evidence17 26 27 51).

Persistence and degree of response

In long-term observational studies, some patients continue to respond for up to 10 years (category C evidence208).

Loss of response to a TNF blocking agent can occur. Failure to respond to one TNF blocking agent does not preclude response to another (category B, D evidence209 210). Patients have been switched successfully from one TNF blocking agent to another.

2009 Update:

Several retrospective and observational studies suggest the efficacy of this switch of TNF blocking agents. One recent randomised controlled trial supports this regimen (category B, D evidence211 212 213 214 215).

Observational data suggest the possibility that primary non-responding patients are less likely to respond to a second TNF blocking agent. Patients who have not tolerated one TNF blocking agent may respond to a second but are also less likely to tolerate a second TNF blocking agent (category B, D evidence200 208 209). The optimal treatment of patients not responding to TNF blockers remains to be determined (category B evidence116 161 166 170).

2009 Update:

Patients with high or moderate disease activity at baseline can respond well to TNF blocking agents (category C evidence216 217).

Golimumab (approved in Canada and USA) has demonstrated similar efficacy in clinical trials as other anti-TNF agents in improving signs and symptoms of patients with RA.218 219 More extensive long-term safety data are needed to establish its place in the TNF blocking agent armamentarium.

Structural changes

TNFα blocking agents slow and/or inhibit radiographic progression in RA, even in some patients without a clinical response (category A evidence220 221). Better clinical and radiological outcomes are achieved when TNFα blocking agents are used in combination with a traditional DMARD (category A evidence222).

Pharmacoeconomic data

Evidence has become available that TNF blocking agents are cost effective from a societal perspective, although this is highly dependent upon the specific circumstances of the analysis and the society in which the analysis is done (category B evidence106 223 224 225 226).

Juvenile idiopathic arthritis (JIA)

Dosing and time to response

TNFα blocking agents, when given up to the maximum approved dosing regimens for polyarticular JIA, usually lead to an early significant, documentable improvement in symptoms, signs and/or laboratory parameters.

Comparing TNFα blocking agents in JIA

Etanercept appears less effective in patients with systemic-onset JIA than in patients with other forms of JIA, There are no prospective studies in children less than 4 years of age; however, some observational registry data suggest comparable efficacy and safety in JIA not of the systemic-onset subtype, As for other subtypes of JIA, there is no evidence that any one TNFα blocking agent should be used before another one can be tried, just as there is no evidence that any TNF blocker is more effective than any other. In JIA-associated uveitis, adalimumab and infliximab appear to be effective more often than etanercept.

Structural changes in JIA

TNFα inhibition contributes to restoration of growth velocity in children whose JIA-associated inflammation is controlled. Bone density improves after treatment with TNFα blocking agents even in patients who have incomplete disease control.

Psoriatic arthritis (PsA)

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has developed treatment recommendations for PsA based on a systematic evidence-based review of the efficacy of TNF blocking agents and other treatments for the various domains of PsA (joints, enthesitis, dactylitis, spine and skin).177

2009 Update:

In addition to efficacy in joints and skin, efficacy has been demonstrated with TNF blocking therapy for enthesitis, dactylitis, function, QoL, fatigue, productivity, work disability and inhibition of structural damage (category A, B, D evidence.75 177 183 184 227 228 229 230 231 232 233 234).

No efficacy differences among TNF blocking agents were found when treating PsA (category A, C evidence226 231). A recent meta-analysis of randomised trials suggests that the efficacy of TNF blocking antibodies may be better than that of soluble receptor with respect to skin manifestations (category C evidence235).

Dosing and time to response

2009 Update:

Improvement of signs and symptoms, function and QoL occurs within 12 weeks. Some patients continue to improve to week 24. For etanercept, 100 mg/week was more effective than 50 mg/week for skin but not joint manifestations (category D evidence236).

Comparing TNFα blocking agents in PsA

Preliminary data suggest that one can sometimes achieve benefit for PsA-related joint and skin signs and symptoms by switching to a different TNFα blocking agent, even if efficacy from a previous anti-TNF agent was never achieved (category C evidence237).

Structural changes in PsA

Durability of clinical efficacy and radiographic data at 2 years in PsA has been demonstrated with etanercept, infliximab and adalimumab (category A, B, C evidence232 234 236).

2009 Update:

Golimumab, a human TNF blocking therapy, is approved in Canada and the USA for PsA. It improves signs and symptoms in joints, skin, nails, enthesitis and dactylitis, as well as function and QoL at 24 and 52 weeks (category A, D evidence238) in both 50 and 100 mg monthly subcutaneous dosing regimens.

Ankylosing spondylitis (AS)

In clinical trials, improvement in signs and symptoms was seen after TNF blocking agents, using patient-reported outcomes (BASDAI, BASFI, patient global VAS, SF-36, spinal mobility measures, peripheral arthritis, enthesitis and acute phase reactants (category A, B, D evidence239 240 241 242 243).

Both infliximab and adalimumab are efficacious in active inflammatory bowel disease, which can be associated with AS.

2009 Update:

Two recent placebo-controlled trials have shown significant efficacy in signs and symptoms in patients with non-radiographic axial spondyloarthritis (category A, D evidence238 242) and according to the Assessment of Spondylo-Arthritis International Society (ASAS) axial criteria (category A evidence244).

There is evidence that the incidence of uveitis flares is reduced when patients are treated with TNF blocking agents (category B, C, D evidence245 246 247).

Regular treatment with infliximab was more effective than “on demand” treatment for AS (category A evidence248). Observational studies indicate that switching to a second TNF blocking agent may be effective (category C, D evidence237).

There is no evidence that any TNFα blocking agent is more effective than any other. No dose-ranging studies have been done with any of these drugs.

The ASAS has published recommendations for the use of TNFα blocking agents in AS (category A evidence244).

Dosing

The approved doses of TNF blocking agents for treatment of AS are 5 mg/kg infliximab 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, B evidence249 250 251; category D evidence214 217 218).

Time to response

A reduction 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. Response may be delayed for up to a year (category D evidence252).

Comparing TNFα blocking agents in AS

There is no evidence that any TNF blocking agent is more effective than any other (category A, B, D evidence186 187 188 189 190 191 192 193 239 240 241 242 243).

Persistence in AS

2009 Update:

A recent randomised controlled trial demonstrated no superiority of a combination of MTX with infliximab versus infliximab alone in the treatment of active AS over 1 year (category B evidence71).

Three TNF blocking agents (adalimumab, etanercept, infliximab) maintain efficacy for 2–7 years in open-label studies. Flare usually occurs after discontinuation of TNF blocking agents (category B, C evidence253 254 255). When TNF blocking agents are restarted, recapture occurs in over 80% (category D evidence254).

Structural changes

Several studies have shown that active inflammation of the sacroiliac joints and spine, as shown by MRI or radiograph, is significantly reduced for up to 3 years by adalimumab, etanercept and infliximab (category A evidence240 242 250; category D evidence251).

Inhibition of new bone formation when using TNF blocking agents has not been demonstrated radiographically (category A, C evidence241 242).

Pharmacoeconomic data in AS

The use of TNF blocking agents reduces the indirect costs of AS (category D evidence256).

Appendix 3 provides a reference listing of other conditions in which TNFα blocking agents have been used.

Safety (arranged alphabetically)

General reviews of TNFα blocking agent safety have been published (category B, C evidence107 257 258 259).

Autoimmune-like syndromes

Antiphospholipid and lupus-like syndromes have occurred in both adult and paediatric patients during treatment with TNF blocking agents. Autoantibody formation is common after TNF blocking agent therapy (eg, antinuclear antibodies), but clinical syndromes associated with these antibodies are rare (category C evidence260 261 262).

Cardiovascular

Treatment of non-RA patients with advanced chronic heart failure with TNF blocking therapy was associated with greater morbidity/mortality (infliximab) or lack of efficacy (etanercept). Studies that examined the risk of heart failure in patients with RA treated with TNFα blocking agents have shown inconsistent results (category B evidence263 264 265).

2009 Update:

The effect of TNF blocking agents on lipids is controversial (category D evidence266 267 268 269 270 271 272). Several studies showed decreased cardiovascular events (myocardial infarction, stroke or transient ischaemic attack) (category D evidence273 274).

Haematological

Rare instances of pancytopenia and aplastic anaemia have been reported (category A, C evidence275). If haematological adverse events occur, TNFα blocking agents should be stopped and patients evaluated for evidence of other underlying disease or association with concomitant drugs.

Transaminase elevation

Rises in liver function tests have been seen in patients treated with adalimumab, infliximab or etanercept, with ALT-AST raised in 3.5–17.6% and increases of these liver enzymes more than twice the upper limit of normal in up to 2.1% (category D evidence276). The use of concomitant drugs and other clinical conditions confound the interpretation of this observation (FDA; category B, C evidence277 278 279 280 281 282 283 284 285). The follow-up and monitoring for increases in liver function test should be governed by the patient’s concomitant drugs, conditions and patient-related risk factors. Worsening of alcoholic hepatitis has been seen in patients receiving TNF blocking agents (category D evidence276).

Infections

Tuberculosis (TB)

An increased susceptibility to TB or reactivation of latent TB has been reported for all TNFα blocking agents. The risk of TB is also increased by the use of corticosteroids.

The clinical manifestations of active TB may be atypical in patients treated with TNFα blocking agents (eg, miliary or extrapulmonary presentations) as has been seen with other immunocompromised patients (category C evidence286 287 288 289). There have been more reported cases of reactivation of latent TB as a proportion of the total number treated in patients using infliximab and adalimumab than in those using etanercept (category C evidence290 291 292 293). This may be due, in part, to differences in mechanism of action, biology or kinetics as compared with the soluble receptor (category D evidence287 289 292) but may also be, in part, because 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. No head-to-head comparisons among TNF blocking agents have been carried out and thus no definitive data on comparisons between these agents are available for the incidence of reactivation of latent TB.

2009 Update:

In a recent survey, done among infectious disease specialists in the United States (an area of low TB prevalence), only 35% of mycobacterial infections among TNF blocking agent users were M tuberculosis. M avium was as frequently found as M tuberculosis and multiple other non-tuberculous mycobacterial infections accounted for the rest of the mycobacterial infections (category C evidence294).

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 evidence295 296 297). Every patient should be evaluated for the possibility of latent TB, including a history that should comprise seeking a history of prior exposure, prior drug addiction or active drug addiction, HIV infection, 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 (category B evidence298; category D evidence299).

In addition, physical examination and screening tests such as tuberculin skin tests (TSTs) and chest radiographs should be carried out before TNFα blocking agent therapy is started, according to local recommendations (category B, C, D evidence257 258 287 290 293 296 297).

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 evidence300). The TST can also be falsely positive owing to prior BCG vaccination. New blood-based diagnostic assays (interferon γ release assays) have been developed using TB-specific antigens. These tests (Quantiferon-Gold and T-Spot TB) have greater specificity for latent TB infection than does the TST, and therefore might provide 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 evidence301 302).

The precise role of these tests in diagnosing latent TB in patients with rheumatoid disease continues to be studied (category C evidence302).

Continued vigilance is required to detect reactivation of latent TB or acquisition of new cases.

2009 Update:

In areas of high TB prevalence (ie, high-risk populations or in the event of potential TB exposure) repeat testing should be considered (category C evidence303 304 305 306).

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 waiting long time periods between initiating preventive treatment and TNF blockade is unnecessary. While there are no prospective trials assessing this question, observational data from Spain suggest that initiating isoniazid treatment 1 month before TNF blockade substantially decreases the risk of latent TB reactivation (category C evidence296 306).

Before starting preventive anti-TB treatment in accordance with local guidelines, consultation with an infectious disease specialist should be considered.

2009 Update:

There are case reports of reinitiation of TNF blocking agents after successful completion of full course antituberculosis treatment (category C evidence307).

Other opportunistic infections

Other opportunistic infections have been reported in patients treated with TNFα blocking agents (category C evidence308 309 310 311 312 313). Particular vigilance is needed when considering patients with infections whose containment is macrophage/granuloma dependent, such as those with listeriosis, non-tuberculous mycobacteria,180 coccidiomycosis or histoplasmosis (including reactivation of latent histoplasmosis (category C, D evidence257 258 259 289 291 308 309 310 311 312).

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 significantly higher than in similar patients treated with DMARDs or corticosteroids (category C, D evidence289 291 293).

Bacterial infections

Serious bacterial infections (usually defined as bacterial infections 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 evidence314 315 316). Risk ratios of 1–3 were documented. TNFα blocking agents should not be administered when serious infections and/or opportunistic infections occur, including septic arthritis, infected prostheses, acute abscess, osteomyelitis, sepsis, systemic fungal infections and listeriosis (category C evidence4 5 161 205 257 258 259 308 309 310 311 312 314 315 316 318).

Treatment with TNFα blocking agents in such patients may be resumed if the infections have been treated adequately (category D evidence; FDA259 287 288 289 298 319).

Other studies indicate that serious infections in certain sites are more common when using TNFα blocking agents, such as the skin, soft tissues and joints, and the risk may be highest during the first 6 months of treatment and possibly increased further in elderly patients. (category C evidence315; category D evidence320).

The possible contribution of previous or concomitant corticosteroids to increasing the risk of infection should always be considered (category B evidence207 315 316).

2009 Update:

Biological agents and high-dose corticosteroid affect acute phase reactions (eg, erythrocyte sedimentation rate, C-reactive protein) irrespective of the cause of the inflammation. Therefore care needs to be exercised to help diagnose infection in the presence of these agents (category C evidence321 322).

The incidence of other bacterial infections (not designated as serious) may be increased when using TNFα blocking agents (relative risk 2.3–3.0, 95% confidence interval (CI) 1.4 to 5.1) (category C evidence314).

The incidence of serious infections is approximately doubled when IL1ra or abatacept is used with any of the TNFα blockers in combination (category A evidence; FDA36 37 113 258 259).

The use of two biological agents in combination is not recommended.

Viral infections

Hepatitis: Patients should be screened for viral hepatitis before TNFα blocking agent initiation, as the long-term safety of TNFα blocking 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 blocking agent therapy. Interestingly, one reported controlled trial of etanercept given adjunctively to standard anti-HCV therapy was associated with significant improvement in liver enzymes, viral load and symptoms (category C, D evidence278 279 285). In hepatitis B, patients treated with all three TNFα blocking agents have experienced increased symptoms, worsening of viral load and in some cases hepatic failure especially after stopping the TNFα blocking agents (category C, D evidence277 285). As a result, specific warnings about hepatitis B reactivation have been added to the US label by the FDA. TNFα blocking agents should not be used in patients with known hepatitis B infection; in the event that hepatitis B infection is discovered during use of TNFα blocking agents, prophylactic antiviral therapy can be employed (category C evidence323).

2009 Update:

A recent observational study reported a small increase risk of H zoster with monoclonal antibodies, while other studies did not report an increased risk (category B, D evidence217 219 321).

Vaccinations

TNFα blocking agents do not usually adversely effect the development of protective antibodies after vaccination with influenza or polysaccharide pneumococcal vaccine, although there is a small decrease in the prevalence of adequate protection and a decrease in the titre of response, especially in combination with MTX (category A, B evidence324 325 326). Vaccination with live attenuated vaccines (eg, nasal flu vaccine, BCG, yellow fever, herpes zoster) is not recommended.

Injection site/infusion reactions

In 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 B evidence4 109 110 111 112 115 116 160 161 162 166 167 190 257). One study indicates that human anti-chimeric antibodies against infliximab were associated with decreased response and increased infusion reactions (category C evidence327).

Acute reactions after infliximab or adalimumab administration are uncommon and are usually mild to moderate, but may, rarely, be serious (category A evidence4 110 161 166 193 219 226; category B, C evidence328). In most instances, infusion reactions can be treated by the use of corticosteroids or antihistamines, or by slowing the infusion rate (category B, C evidence322 327).

Malignancies

The incidence of lymphoma is increased in chronic inflammatory diseases such as RA. This increase is associated with high disease activity (category C evidence329 330). In most studies the risk for lymphoma (especially non-Hodgkin’s lymphoma) is increased two- to fivefold in patients with RA as compared with the general population (category B evidence331 332 333 334 335). A similar risk is seen in patients with RA who have received TNFα blocking agent therapy (category B, C evidence259 329 333 334). It is unclear if the risk is increased (category A, B evidence336 337).

While two meta-analyses of anti-TNF therapies (with infliximab and adalimumab) report a higher rate of solid malignancies, including skin, (category A, C evidence338 339) several other large observational databases and a case–control study did not demonstrate an increased incidence of solid tumours in patients receiving TNFα blocking agent compared with matched controls (category B, C evidence340 341 342 343 344).

2009 Update:

Further studies found no increased risk of solid tumours in analyses of the same data wherein positive associations were previously found (category A, B, C evidence345 346). Neither the duration of treatment nor the duration of follow-up were associated with an increased risk of cancer during the first 5 years of treatment (category B evidence335 345).

The evidence for an increased incidence of non-melanotic skin cancers associated with TNF blocking agents is conflicting (category B evidence345).

In patients at risk for malignancies (eg, smokers) or in patients with COPD, there may be an increased risk of lung cancers. In a trial of patients with COPD assigned to infliximab versus placebo, nine developed lung cancers during the trial and another four lung cancers were found during open-label follow-up (category A evidence341 342). Lung cancer seems to be increased in RA, although whether this is owing to disease activity or confounding factors is not known (category C evidence341 342). 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 evidence343).

The concomitant use of azathioprine with infliximab in adolescents has been associated with the occurrence of rare hepatosplenic lymphomas (category C evidence, FDA). It is not currently known if TNF blockade worsens an underlying malignancy or increases the risk of recurrence (category B evidence344 346).

Vigilance for the occurrence of lymphomas and other malignancies (including recurrence of solid tumours) remains appropriate in patients treated with TNFα blocking agents.

Neurological diseases

Rare instances of central and peripheral demyelinating syndromes including Guillain–Barré syndrome have been reported in patients using TNFα blocking agents (category C evidence347). In some cases, but not all, these syndromes have improved after withdrawal of TNFα blocking therapy and steroids were given. Accordingly, TNFα blocking therapy should not be given to patients with a history of demyelinating disease or optic neuritis (category D evidence348 349 350 351 352).

Risks during pregnancy

2009 Update:

The safety of anti-TNF therapy during pregnancy is unknown. Experts disagree about whether TNF 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 TNF blocking agents, while one recent study did find an increased rate of miscarriages (category D evidence353 354 355).

A rare combination of congenital abnormalities (VACTERL—vertebral abnormalities, anal atresia, cardiac defect, tracheo-oesophageal, renal and limb abnormalities) and partial VACTERL defect have been reported rarely although the risk and causality is unclear (category C evidence356).

Pulmonary

Rare instances of acute, severe and sometimes fatal interstitial lung disease have been reported in patients using TNFα blocking agents (category C evidence357).

Skin disease

2009 Update:

Cases of psoriasis, psoriaform lesions or exacerbation of psoriasis have been reported when using all TNF blocking agents. In some cases, switching TNF blocking agents allowed continuation of treatment without recrudescence of skin lesions (category D evidence358 359 360 361). Additionally rare cases of Stevens–Johnson syndrome, digital vasculitis, erythema multiforme, toxic epidermal necrolysis granulomatous reactions in skin and lungs have been noted (category D evidence362 363 364).

Summary

TNFα blocking agents are effective DMARDs and are a major advance in the treatment of RA, PsA, AS, JIA and anterior uveitis complicating JIA. Their use is expanding to other rheumatic diseases. Studies in selected areas of efficacy, toxicity and general use of TNFα blocking agents are needed to help define further the most appropriate use of these agents. Further considerations when using TNFα blocking agents in these diseases are the balancing of efficacy, toxicity and cost. It is hoped that this statement, based on the best evidence available at this time, and modified by expert opinion, will facilitate the optimal use of these agents.

Other biological agents

Alefacet (approved in the USA for psoriasis but not PsA) is a fully human fusion protein that blocks interaction between LFA-3 on antigen-presenting cells and CD2 on T cells, leading to decreased T-cell activation and deletion of certain T-cell clones. It is approved for the treatment of psoriasis in the USA. A phase 2 trial in PsA demonstrated modest efficacy in joints and skin at 24 weeks. A second course (each course is 12 weekly intramuscular injections followed by 12 weeks without injections) during an open-label extension demonstrated sustained articular efficacy (category A evidence365).

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 leukoencephalopathy.

Ustekinumab is an inhibitor of IL12 and 23 which acts in both the TH17 and TH1 pathways of inflammation and is approved for the treatment of psoriasis, and is given at 0, 4 and then every 12 weeks subcutaneously (category A evidence366). A phase 2 study of patients with PsA, dosed weekly for 4 weeks, showed improvement in the signs and symptoms of PsA at the 12-week primary end point (category A evidence367).

Conclusion

The treatment of RA and other rheumatic diseases and conditions of altered immunoreactivity has changed dramatically for 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 quality of life of patients with these conditions. In addition, this consensus statement should provide evidence-based support for the selection of agents and justification for their use.

Appendices: categories of evidence

  • Category 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 category 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 recommendations 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 randomised controlled trials, non-randomised controlled studies 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.

Appendix 1 Rituximab synopsis

Table A1

ANCA-associated vasculitis

Table A2

Cryoglobulinaemia

Table A3

Sjögren’s syndrome

Table A4

Juvenile idiopathic arthritis

Table A5

Systemic lupus erythematosus

Table A6

Lupus nephritis

Table A7

Idiopathic and inflammatory myopathy/myositis

Table A8

Behçet’s disease

Table A9

Polyneuropathy

Table A10

Demyelinating diseases of the central nervous system

Table A11

Pemphigus, pemphigoid, epidermolysis bullosa and other dermatological diseases

Table A12

Scleroderma

Table A13

Antiphospholipid syndrome

Appendix 2 Anecdotal studies of interleukin 1 receptor antagonist (anakinra)

Table A14

Anecdotal studies of ILlra

Appendix 3 Anecdotal studies of anti-tumour necrosis factor agents

Table A15

Anecdotal studies of antitumour necrosis factor agents

REFERENCES

  1. 1.
  2. 2.
  3. 3.
  4. 4.
  5. 5.
  6. 6.
  7. 7.
  8. 8.
  9. 9.
  10. 10.
  11. 11.
  12. 12.
  13. 13.
  14. 14.
  15. 15.
  16. 16.
  17. 17.
  18. 18.
  19. 19.
  20. 20.
  21. 21.
  22. 22.
  23. 23.
  24. 24.
  25. 25.
  26. 26.
  27. 27.
  28. 28.
  29. 29.
  30. 30.
  31. 31.
  32. 32.
  33. 33.
  34. 34.
  35. 35.
  36. 36.
  37. 37.
  38. 38.
  39. 39.
  40. 40.
  41. 41.
  42. 42.
  43. 43.
  44. 44.
  45. 45.
  46. 46.
  47. 47.
  48. 48.
  49. 49.
  50. 50.
  51. 51.
  52. 52.
  53. 53.
  54. 54.
  55. 55.
  56. 56.
  57. 57.
  58. 58.
  59. 59.
  60. 60.
  61. 61.
  62. 62.
  63. 63.
  64. 64.
  65. 65.
  66. 66.
  67. 67.
  68. 68.
  69. 69.
  70. 70.
  71. 71.
  72. 72.
  73. 73.
  74. 74.
  75. 75.
  76. 76.
  77. 77.
  78. 78.
  79. 79.
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