Article Text

Download PDFPDF

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010
  1. D E Furst1,
  2. E C Keystone2,
  3. J Braun3,
  4. F C Breedveld4,
  5. G R Burmester5,
  6. F De Benedetti5,
  7. T Dörner5,
  8. P Emery6,
  9. R Fleischmann7,
  10. A Gibofsky8,
  11. J R Kalden9,
  12. A Kavanaugh10,
  13. B Kirkham11,
  14. P Mease12,
  15. J Sieper12,
  16. N G Singer13,
  17. J S Smolen14,
  18. P L C M Van Riel15,
  19. M H Weisman16,
  20. K Winthrop17
  1. 1University of California at Los Angeles, Los Angeles, California, USA
  2. 2University of Toronto, Toronto, Canada
  3. 3Rheumazentrum Ruhrgebiet, Herne, Germany
  4. 4Leiden University Medical Centre, Leiden, The Netherlands
  5. 5Laboratorio di Reumatologia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
  6. 6Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, UK
  7. 7University of Texas Southwestern Medical Center, Dallas, Texas, USA
  8. 8Rheumatology/Medicine Hospital for Special Surgery, New York, New York, USA
  9. 9University of Erlangen-Nuremberg, Erlangen, Germany
  10. 10Rheumatology/Allergy Immunology, University of California, San Diego, San Diego, California, USA
  11. 11Rheumatology Department/Guys Hospital, London, UK
  12. 12Swedish Medical Center and University of Washington, Seattle, Washington, USA
  13. 13Division of Rheumatology, MetroHealth Medical Center/Case Western Reserve Society, Cleveland, Ohio, USA
  14. 142nd Department of Medicine, Krankenhaus Lainz and Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria
  15. 15Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands
  16. 16Cedars Sinai Medical Center, Los Angeles, California, USA
  17. 17Oregon Health and Science University, Portland, 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

Statistics from Altmetric.com

Introduction

As in previous years, the consensus group to consider 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 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, B cell-specific agents, interleukin 1 antagonists (IL-1), tocilizumab and tumour necrosis factor α (TNFα) blocking agents, an update of the previous consensus 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 possible. 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, 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 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 doctors to use these drugs in exceptional (‘off-label’) circumstances.

General statements

The formatting of this document is arranged as follows: general introduction and general statements 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 indications occurs when appropriate safety is arranged together after clinical use, in alphabetical order.

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, validated quantitative measures for clinical trials can be used, such as Disease Activity Score, Simplified 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 trials 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 biological agents in the rheumatic diseases. For all but the TNFα and IL-1 blocking agents, there are too few data to draw any conclusions. Since a lack of association is extremely difficult 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 designation while TNFα and IL-1 blocking agents are designated as category B (see specific drugs).

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 the data regarding 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. To enable ease of reference, the biological agents are listed in alphabetical order: abatacept; B-cell therapy; IL-1 blocking agents; tocilizumab; TNF blocking agents.

Abatacept

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

Indications

Rheumatoid arthritis

Abatacept 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 combination 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 (category C evidence12). Abatacept has been used with MTX and other DMARDs. (category A, B evidence10 11 13,,17).

Juvenile idiopathic arthritis

Abatacept is recommended for treatment of active polyarticular 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 insufficient response to other DMARDs, including at least one TNFα blocking agent.

Clinical use

Dosing

Rheumatoid 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 response

Some 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 treatment. (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-effectiveness

Abatacept appears cost-effective and comparable to other biological agents (category B effective14 23,,26).

Persistence

Some 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 agents

In a controlled trial, the clinical efficacy of abatacept (10 mg/kg) was similar to low dose infliximab (3 mg/kg); these were numerically fewer serious adverse events in the abatacept treated patients (category A evidence28).

Structural changes

Abatacept in combination with MTX inhibits or reduces radiographic 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 arthritis

Dosing

Abatacept 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 response

While 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).

Safety

Autoimmune disease

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

Infections

Tuberculosis

All patients in abatacept phase III trials were screened for tuberculosis (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 (category 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 significantly 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 (category C evidence33).

For abatacept 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 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.

Malignancies

One 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 abatacept clinical trial data were compared with national registries, no increased rates of lymphoma, lung, breast, colorectal or total malignancies were found, although the control populations 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 monitoring is necessary. (category C evidence37)

Vaccinations

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, comparable to previous reports in patients with RA receiving MTX (category D evidence39).

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 pregnancy when using abatacept for any definite 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 benefits may justify potential risks.’

Rituximab 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.

A consensus statement on the use of rituximab in patients with RA has been published (category D evidence40).

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 for whom at least one TNFα blocking agent has produced an inadequate 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 citrullinated 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 use

Dosing

Rituximab is administered intravenously as two 1 g or two 500 mg rituximab infusions (given with 100 mg methylprednisolone 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 (category D evidence41 46 50 53).

Time to response

In clinical trials, rituximab results in significant improvement in signs and symptoms and/or laboratory measures by 8–16 weeks (category A, D evidence56,,63).

Persistence

Rituximab 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 (category A, B evidence41 56 60 62,,65).

2010 Update:

Studies have shown that repeated treatment courses are effectivein previously responsive patients with RA (category C, D evidence61 64).Open-label extension studies of up to 6 years showed continued response (category D evidence66). Most of the patients who received subsequent courses did so24 weeks or more after the previous course and none received repeatedcourses earlier than 16 weeks after the previous course (category B, D evidence65 66). Treatment with rituximab every 6 months demonstrated better clinical efficacy than on-demand treatment without significantly increasing adverse events (category B evidence65). There are conflicting data on the efficacy of re-treatment of initial non-responders (category C evidence67).

Degree of response

In 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, disability and QoL (category A, evidence71 72). Data from randomised controlled trials (RCTs) show that the combination of rituximab with MTX yields better clinical efficacy for RA than monotherapy (category A evidence42 46 51 60). Preliminary data of non-interventional studies69 70 suggest that combination with leflunomide yields even higher responses than with MTX.

Structural changes

Rituximab 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 evidence). In RA, at 1 year, rituximab in combination with MTX, the 1000 mg×2, regimen, reached the primary end point of protection against radiographic progression compared with MTX alone (category B evidence73).

Safety

Hepatitis

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)

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 TNFα non-responders, patients with active TB were excluded. Others were screened by chest radiograph 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 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 receiving 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 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 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 confirmed 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 combination with adalimumab or etanercept, no significant increase of serious infectious events over 6 months was observed (category C evidence86)

Infusion reactions

The most widespread adverse events are infusion reactions, which are most common with the first infusion of the first course (up to 35%) and are reduced with the second and subsequent infusion (about 5–10%). Intravenous corticosteroids were shown to reduce the incidence and severity of infusion reactions by about 30% without changing efficacy (category A, C and D evidence41 42 44 46 51,,53). Rare anaphylactoid reactions have occurred when rituximab is used (category C evidence).

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 evidence66).

Neurological syndromes

Cases 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 studies and animal studies either show risk or are lacking. However, potential benefits 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 reactions

Rare 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 (category D evidence92 93). The causative role of rituximab in these circumstance remains unknown.

Vaccination

In a controlled trial, rituximab significantly decreased the immune response to neoantigen, (keyhole limpet haemocyanin) and pneumococcus, whereas delayed-type hypersensitivity responses and responses to tetanus were unchanged (category A evidence94).

2010 Update:

Humoral responses to influenza 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 influenza 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 influenza 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 influenza, should be given before starting 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 agents

One 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).

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 evidence102,,104). 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 evidence,99 100 105 category C evidence106). No trials of anakinra as the first DMARD for patients with early RA have been published.

Cryopyrin-associated periodic syndromes

Rilonacept and canakinumab have major clinical benefit in children and adults with CAPS, including severe familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous, articular syndrome, familial cold autoinflammatory syndrome/familial cold urticaria (category 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 efficacy 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 benefit in CAPS.97 98 107,,109 Canakinumab is administered subcutaneously 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 disease

IL-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 PsA

Anakinra has been evaluated in two open-label studies of AS, but without consistent evidence of efficacy.582 583 Anakinra did not demonstrate clinical efficacy in PsA.584

Crystal-associated arthropathies

There are anecdotal reports of clinical efficacy following treatment with anakinra in patients with intractable gout585 and pseudogout.586

Other arthropathies

Treatment with intra-articular anakinra was evaluated in a randomised clinical trial of patients with osteoarthritis (category A evidence587). Treatment was well tolerated but no improvements were observed compared with placebo.

Anakinra has been used with effect in CAPS, familial Mediterranean fever, the TNF receptor-associated periodic syndrome, deficiency of the interleukin-1-receptor antagonist and Schnitzler syndrome.

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 inhibit or induce slowing of radiographic progression (category A evidence99 102 103 111). If improvement is not seen by 16 weeks, discontinuation of anakinra should be considered.

Comparison with TNFα blocking agents

2010 Update:

A recent meta-analysis demonstrates that anakinra is less effective than the TNFα inhibitors in treating RA (category A evidence90)

Safety

These 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).

Infections

Tuberculosis

To date, there is no indication that use of anakinra is associated with an increased incidence of TB (category D evidence77).

Bacterial infections

The 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 continue 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 efficacy. However, an increase in the incidence of serious infection was observed in comparison with either compound used as monotherapy. Therefore, the combination of anakinra and etanercept should not be prescribed (category A 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 evidence99 102 119).

Pregnancy

See 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.

Vaccinations

In one controlled trial, anakinra did not inhibit antitetanus antibody response (category D evidence111).

Tocilizumab

Tocilizumab is a humanised anti-IL-6 receptor monoclonal antibody (category A, D evidence120,,126).

Indications

Rheumatoid arthritis

Tocilizumab has been approved in the European Union and a number of other countries in combination with MTX (category 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 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 insufficient response (category A, D122 138).

JIA and other indications

In Japan and India, tocilizumab has also been approved for systemic JIA based on a small open 19-patient study of systemic- onset JIA and multicentric Castleman's disease (category A evidence132 139 140).

Clinical use

Tocilizumab 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 (category A, D evidence124 136 141) or DMARD inadequate responders (category A, D122 138).

Dosing

The dosing regimens recommended vary by indication and country so they are shown in Table 1. Tocilizumab is administered 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.

Table 1

Tocilizumab: Dosing regimens and 2010 update

2010 Update:

The 2010 update is shown in Table 1.

Tocilizumab has been used in JIA-associated arthritis (class A evidence134).

Timing of response

Onset of response can occur as early 2–4 weeks in some patients but it may take ≥24 weeks in other patients (category 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 agents

Tocilizumab has not been compared directly with TNFα blocking agents. It can be used after failure of one or more TNFα inhibitor (category A, D evidence123 137).

Structural changes

Tocilizumab 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 reduces radiographic progression as monotherapy (category A evidence133 145).

Safety

Cardiovascular 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-density 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 effective in reducing lipids (category D evidence161).

Gastrointestinal

In 6-month controlled clinical trials, generalised peritonitis, lower gastrointestinal perforation, fistulae 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-inflammatory drugs may increase the risk of these events. Tocilizumab should be used with caution in patients with a history of intestinal ulceration or diverticulitis (category D evidence162).

Haematological

Neutropenia A higher proportion of patients treated with tocilizumab had a decrease in the absolute neutrophil count compared with placebo. A few patients had a decrease of polymorphonuclear 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 according 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).

Vaccination

Safety and response to vaccinations were evaluated in patients with RA receiving tocilizumab. Most patients could be effectively immunised with influenza and pneumococcal vaccine (category D evidence169). As for the other biological agents, live vaccines should not be given while patients are receiving tocilizumab (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 bilirubin, 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 failure or liver damage have been documented (category A, D evidence120,,125 132,,134 141 148 154,,156 163 164 169 172,,174).

Infections

Bacterial infections

In a 6-month controlled clinical study, the rate of serious infections 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 trials (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, careful 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 infections

Cases 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 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 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 events

Serious infusion reactions during/after treatment with tocilizumab are uncommon (category A, D178)

Malignancies

There is no evidence that tocilizumab therapy is associated with an increased incidence of malignancies in patients with RA (category 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 benefits may justify potential risks.’

Skin

Erythroderma has been ascribed to tocilizumab (category D evidence179).

TNFα blocking agents

TNFα 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 discussed, where appropriate.

Indications

Rheumatoid arthritis

In 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 sulfasalazine and leflunomide. 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 first DMARD in some patients (category A evidence90 113 117 180,,189 194; category A, B evidence35 116 117 123 186 190 195,,197). Adalimumab, certolizumab, etanercept and golimumab are 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 evidence198,,200). The combination of a TNFα blocking agent and MTX yields better 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 traditional DMARDs is clinically as effective as a combination of MTX plus etanercept (category A evidence158).

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 as monotherapy and with background MTX. (category A, B evidence147 170 171 204,,222).

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 evidence196 223,,231). There is no evidence that combination therapy with conventional DMARDs is better than monotherapy.

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 evidence771).

Juvenile idiopathic arthritis

Etanercept 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) Infliximab was beneficial at 6 mg/kg in polyarticular JIA (category A evidence232 233 238 239).

2010 Update

A recent meta-analysis of RCTs demonstrated that etanercept, infliximab and adalimumab were more effective than anakinra in RA (category A evidence122).

Clinical use

Rheumatoid arthritis

Dosing

Increasing the dose or reducing the dosing intervals of infliximab may provide additional benefit in RA, whereas increased doses of etanercept or certolizumab have no increased benefit at a group level (category A, B evidence197 232 240,,243). The addition or substitution of other DMARDs may increase efficacy 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 significant, 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 significant 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 infliximab (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 blocking agent to another. Several retrospective and observational studies suggest the efficacy 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 second 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 (category C evidence141 181 184 189 199 224 232 264).

Patients with high or moderate disease activity at baseline can respond well to TNFα blocking agents (category C evidence264 265).

Structural changes

TNFα blocking agents inhibit or reduce radiographic progression 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 blockers are used in combination with a traditional DMARD (category A evidence270).

Pharmacoeconomic data

TNFα blocking agents may be 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 evidence120 182 271,,281).

2010 Update in RA:

Golimumab and certolizumab pegol have been recently approved for the treatment of RA and demonstrated efficacy in clinical trials similar to that of other TNFα blocking 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 profile 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 arthritis

Dose

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. 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 efficacy 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 infliximab appear to be effective more often than etanercept (category C, D evidence286 287).

2010 Update:

Some observational registry data suggestcomparable efficacy and safety in polyarticular JIA as in the systemic- onsetsubtype (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% flared when the TNFα blocking agent was stopped (category C evidence234).

Structural changes

TNFα blocking agents contribute to restoration of growth velocity in children whose JIA-associated inflammation is controlled. Bone density improves after treatment with a TNFα blocking agent even in patients who have incomplete disease control (category C, D evidence234,,238).

Psoriatic arthritis

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis has developed treatment recommendations for PsA based on a systematic evidence-based review of the efficacy of TNFα blocking agents.216

In addition to efficacy in joints and skin, efficacy has been demonstrated with TNFα blocking agent therapy for enthesitis, dactylitis, function, QoL fatigue, productivity, work disability 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, followed 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 efficacy 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 benefit for PsA-related joint and skin signs and symptoms by switching to a different TNFα blocking agent, even if efficacy from a previous TNFα blocker was never achieved (category C evidence293).

Persistence

Durability of clinical efficacy and radiographic data up to 2 years in PsA has been demonstrated with etanercept, infliximab and adalimumab (category A, B, C evidence220 221).

2010 Update

Golimumab 50 and 100 mg given once monthly shows similar clinical efficacy for up to 104 weeks.

The golimumab and certolizumab safety profile is similar to that seen for other anti-TNF agents (category B evidence290 295 296).

Ankylosing spondylitis

In clinical trials in patients fulfilling the modified New York criteria 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 significant efficacy 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 infliximab over infliximab alone in the treatment of active AS over 1 year (category B evidence72 196 223). Regular treatment with infliximab 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).

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 flares 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 efficacious (category D evidence303 315).

Dosing

The approved doses of TNFα 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 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 efficacy 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 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 (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, infliximab) maintained efficacy for 2–7 years in open-label studies. The disease usually flares 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 inflammation of the sacroiliac joints and spine, as shown by MRI, is significantly reduced for up to 3 years by adalimumab, etanercept, infliximab and golimumab (category A, B, C evidence302 304 311 316).

Patients with AS who received TNFα blocking agents showed significant 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).

Antibodies directed against adalimumab or infliximab 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 indications

General 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 failure with TNFα blockers 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 blockers have shown inconsistent results (category B evidence261 262 323).

On the other hand, several studies showed decreased cardiovascular 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 conflicting (category D evidence318,,320 326,,329).

2010 Update

A review (category C evidence262 330) and multiple open studies of TNFα blocking agents have been published (category C, D evidence329,,333). Infliximab, etanercept and golimumab are reported to improve lipid and arthrogenic profiles, reduce arterial stiffness and decrease insulin 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 infarctions was found (category C evidence324 336). To date these profiles seem to reflect the degree to which inflammation is controlled. Better disease control was reflected in either unchanged or improved lipid profiles, whereas incomplete control was associated with worsening profiles. The clinical significance 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 infliximab, 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 the interpretation of this observation (FDA; category B and C evidence289 337 338,,342). 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 TNFα blocking agents (category C evidence337).

2010 Update:

Golimumab and certolizumab, like the other TNFα blocking agents, are subject to liver function test elevations (category A, C, D evidence295 343,,348).

Infections

Tuberculosis

An 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, infliximab 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 kinetics as compared with the soluble receptor (category C, D evidence295 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 immunocompromised 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 reactivation in patients using adalimumab or infliximab to be significantly higher than in patients using etanercept (category C evidence353 354).

TB risk data for golimumab and certolizumab are limited. Trials of golimumab exclude patients with active or latent TB and cases of TB were uncommon (category B evidence295). In trials of certolizumab there was an increased incidence of TB relative to controls, but TB screening procedures 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 mycobacterial infections accounted for the rest of the mycobacterial infections (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 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 evidence275 358).

In addition, physical examination and screening tests such as TSTs and chest radiographs should be carried out before treatment with TNFα blocking agents is started, according to local 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-specific antigens. These tests (Quantiferon-Gold In-tube and T-Spot TB) have greater specificity for latent TB infection than 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 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 ongoing 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 reactivation 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 initiating isoniazid therapy 1 month before TNF blockade substantially 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 infectious 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 infections

Other 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 infections whose containment is macrophage/granuloma dependent, such as those with listeriosis, non-tuberculous mycobacteria (category D evidence361 372), coccidiomycosis or histoplasmosis (including reactivation 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 significantly higher than in similar patients treated with DMARDs or corticosteroids (category C and D evidence357 369).

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 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 (category 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 first 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 inflammation. 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, etanercept and etanercept plus MTX groups (category C evidence20).

Viral infections

Hepatitis

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 blocking agents (category C, D evidence279 289 309 339 340 341 375). 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 evidence376). In hepatitis B, patients treated with adalimumab, etanercept and infliximab 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).

Specific 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 evidence 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).

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 significantly lower risks for etanercept and adalimumab than for infliximab (category D and B evidence277 377).

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 A, B evidence90 113 117 181 265 305 323). One study indicated that human antichimeric antibodies against infliximab were associated with decreased response and increased infusion reactions (category C evidence285).

Acute reactions after adalimumab, golimumab administration 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).

Malignancies

The incidence of lymphoma is increased in chronic inflammatory 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 fivefold 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 blocking therapy (category A, B, C evidence315 323 380,,387). It is unclear if the risk of lymphoma is increased.

While two meta-analyses (with infliximab and adalimumab) report a higher rate of solid malignancies, including skin (category A evidence388 389), several other large observational databases 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 evidence315 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 associated with an increased risk of cancer during the first 5 years of treatment (category B evidence392).

The evidence regarding an increased incidence of non-melanotic skin cancers associated with TNFα blocking agents is conflicting (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 infliximab versus placebo, nine developed lung cancers during the trial and another four lung cancers were found during an open-label follow-up (category A evidence396 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).

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 increase the risk of recurrence (category B evidence384 394).

Vigilance for the occurrence of lymphomas and other malignancies (including recurrence of solid tumours) remains appropriate 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 cancer 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 malignancies but was associated with lymphoma (category B evidence296).

Neurological diseases

Rare instances of central and peripheral demyelinating syndromes, 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 demyelinating disease, multiple sclerosis or optic neuritis (category C, D, evidence398,,407).

2010 Update:

The demyelinating events tend to occur within the first 5–8 months of use (category C evidence400 406).

Risks during pregnancy

The 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 studies 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 definite 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, finding an approximately 3% transfer of etanercept from serum to placenta and no transfer of etanercept in breast milk (category D evidence411). These data, if corroborated will help guide advice to mothers treated with TNFα blocking agents.

Male sexual function

In limited data, sperm volume and function were not different from normal. Men using TNFα blocking agents can father normal children, and sexual function seems either unaffected or improved (category C evidence412).

Pulmonary

Rare instances of acute, severe and sometimes fatal interstitial lung disease have been reported in patients using TNFα blocking agents (category C evidence413).

Skin disease

Cases of psoriasis, psoriaform lesions or exacerbation of psoriasis 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 epidermal 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.

Vaccinations

Appropriate vaccinations should be carried out before initiating treatment with TNFα blockers, according to national guidelines.

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 evidence280 281 284). Vaccination with live attenuated vaccines (eg, nasal flu vaccine, BCG, yellow fever, herpes zoster) is not recommended, though vaccination with MMR with appropriate memory vaccine response has been reported in patients with JIA treated with etanercept and MTX (category D424).

Other biological agents

Alefacept is approved in the USA for psoriasis but not PsA.

Alefacept 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. A phase II trial in PsA demonstrated modest efficacy 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 demonstrated sustained articular efficacy (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 inflammation and is approved for the treatment of psoriasis, given at 0, 4 and then every 12 weeks subcutaneously (category B evidence426).

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 QoL 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 Abatacept

JIA-associated uveitis may improve with abatacept treatment (category C evidence427).

Table A1

Anecdotal studies using abatacept

Appendix 2 Rituximab

Table A2

Anecdotal studies using rituximab

Appendix 3 IL-1 blocking agents

Table A3

Anecdotal studies using interleukin 1 inhibitors

Appendix 4 TNFα blocking agents

Table A4

Anecdotal studies of antitumour necrosis factor agents

Appendix 5 Anecdotal studies using tocilizumab

Tocilizumab to include iritis (JIA) in a dose of 8 mg/kg every 2 weeks (category A evidence134) and in polyarticular JIA (category A, D evidence132).

References