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Practice Therapeutics

# Biologicals for rheumatoid arthritis

BMJ 2011; 343 (Published 28 July 2011) Cite this as: BMJ 2011;343:d4027
1. Peter Tugwell, professor of medicine 1,
2. Jasvinder A Singh, associate professor of medicine2,
3. George A Wells, professor of epidemiology and community medicine3
1. 1Department of Medicine, Institute of Population Health, and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5
2. 2Department of Medicine, Birmingham VA Medical Center and University of Alabama at Birmingham, Birmingham AL 35294, USA
3. 3Department of Epidemiology and Community Medicine, University of Ottawa, and University of Ottawa Heart Institute, Ottawa
1. Correspondence to: P Tugwell tugwell.bb{at}uottawa.ca

#### Case scenario

A 45 year old woman had seropositive erosive rheumatoid arthritis diagnosed three years ago with involvement of the hands, wrists, shoulders, and feet. She found it difficult to dress, cook, do the housework, and control her dog on her morning walk. She improved initially on triple disease modifying antirheumatic drug (DMARD) therapy (methotrexate 25 mg intramuscularly weekly with oral folic acid 1 mg daily, hydroxychloroquine 400 mg daily, sulfasalazine 1 g twice daily) and naproxen 500 mg twice daily. Her symptoms have now flared up despite continuation of triple DMARD therapy, with multiple swollen and tender joints. Radiographs show that since last year she has developed three new erosions in her metacarpophalangeal joints. She wants to discuss the new biological drugs that you mentioned would be an option if she did not respond to the above therapy

The term biological describes treatments developed and produced in live cell systems. The drugs may also be referred to as biological therapies or cytokine modulators.1 By targeting molecules involved in the inflammatory response, such as tumour necrosis factor-α, some biologicals help to reduce or suppress inflammation, potentially reducing joint damage in rheumatoid arthritis. They are used for an increasing number of indications and are approved in some countries for conditions such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. Most of these conditions are autoimmune diseases characterised by upregulation of cytokines such as interleukins; tumour necrosis factor and T and B lymphocytes contribute to the inflammation, a central pathophysiological feature of these conditions. The following are approved for treatment of rheumatoid arthritis in the United Kingdom or the United States, or both:

• Five tumour necrosis factor inhibitors: adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade)

• Anti-interleukin 1 therapy: anakinra (Kineret)

• T cell costimulator modulator: abatacept (Orencia)

• Anti-CD20 therapy: rituximab (Rituxan or MabThera)

• Anti-interleukin 6 receptor therapy: tocilizumab (marketed as RoActemra in Europe and Mexico, and as Actemra in other countries).

Box 1 explains how traditional disease modifying antirheumatic drugs (DMARDs) work compared with biologicals.

#### Box 1 Mechanisms of action: traditional DMARDs versus biologicals

Traditional disease modifying antirheumatic drugs (DMARDs) are medications such as methotrexate, sulfasalazine, and hydroxychloroquine that modify the underlying systemic inflammatory process of rheumatoid arthritis by their impact on synovitis and bone and joint destruction. Traditionally this response manifested as improvement in swollen and painful joints, improvement in erythrocyte sedimentation rate (a marker of inflammation), and slowing of radiographic progression. In contrast, medications such as non-steroidal anti-inflammatory drugs provide symptomatic relief but do not alter the course of the condition. The various mechanisms of action of DMARDs include inhibition of purine or pyrimidine synthesis with methotrexate, azathioprine, and leflunomide; induction of apoptosis of inflammatory cells with sulfasalazine or hydroxychloroquine; and inhibition of T lymphocytes with ciclosporin. In contrast, several of the biologicals have more specific cytokine targets—for example, inhibition of tumour necrosis factor-α with etanercept, adalimumab, infliximab or of interleukin 6 with tocilizumab. Two anticipated advantages with the new biologicals were improved clinical efficacy and halting of joint destruction in combination with DMARDs, and a better safety profile.

## How do the biologicals compare with other drugs?

Recent guidelines from the National Institute for Health and Clinical Excellence (NICE), based on a systematic review and considerations of cost effectiveness, recommend that in addition to low dose glucocorticoids, two trials of six months of traditional DMARD monotherapy or combination therapy (at least one including methotrexate) should fail to control symptoms or prevent disease progression before a biological is recommended.1

Consensus recommendations from the American College of Rheumatology2 and the European League Against Rheumatism,3 also based on systematic reviews, give similar advice. In patients with low clinical, radiological, and serological activity, they recommend use of biologicals only in patients for whom traditional DMARDs (monotherapy or combination therapy, including methotrexate, leflunomide, hydroxychloroquine, sulfasalazine) fail. In patients with poor prognostic markers (high disease activity, progressive disability, and/or changes in radiographs, nodules) they recommend biologicals in patients who do not respond to traditional DMARD monotherapy. They also recommend consideration of economic concerns related to the use of these treatments.

Whether patients should be allowed to begin taking biological DMARDs without first failing combination traditional DMARDs is still undecided. One meta-analysis has shown that aggressive combination therapy with two to three DMARDs (most often two or three of methotrexate, sulfasalazine, hydroxychloroquine, leflunomide) plus glucocorticoids reduced radiographic joint destruction, compared with single traditional DMARD therapy.4 Yet two other systematic reviews found no such benefit.5 6 A randomised controlled trial is under way to test this further by comparing the combination of methotrexate, hydroxychloroquine, and sulfasalazine to a combination of methotrexate and etanercept in 600 patients with rheumatoid arthritis.7

## How well do biologicals work?

We recently published a Cochrane network meta-analysis of 27 studies containing 7643 patients taking six biologicals (abatacept, adalimumab, anakinra, etanercept, infliximab and rituximab).8 We did an adjusted indirect comparison using a generalised mixed model approach. For this article we have updated this to include all nine biologicals (40 studies containing 12 161 patients).

As shown in figure 1 and the table, in patients with an inadequate response to methotrexate, compared with placebo the use of biologicals was associated with a number needed to treat of three in achieving an “ACR 50” improvement (defined as a 50% improvement in patient and physician reported criteria of the American College of Rheumatology—see footnote in table for fuller definition).8 Each biological was significantly more likely than placebo to achieve an ACR 50 (fig 1). Five year observational registry data show that over five years 30% of patients discontinue tumour necrosis factor inhibitors, but those who continue taking the biological maintain the degree of ACR 50 benefit over the five years.9

Fig 1 Comparison of each biological drug with placebo for benefit (ACR 50). Data adapted from Singh et al8. All trials meeting the eligibility criteria and using the doses approved by the US Food and Drug Administration were included as specified in the methods of the Cochrane overview.6 The longest follow-up in truly blinded phase was used

Summary of findings from Cochrane reviews of biologicals for rheumatoid arthritis (values adjusted for control event rate)8 10

View this table:

Remission (elimination of all symptoms and signs) occurs rarely. Prevention of irreversible joint destruction is generally thought to be a major potential benefit of biologicals in rheumatoid arthritis, and although controlled trials report only one year of radiographic data, these show a relative effect of 66% (2.44/3.7 × 100) reduction in radiographic progression. This is only a small absolute reduction (<1%) as the scale is 0-440 over 26 joint areas. However, as joint destruction in only a few joints may lead to disability, a reduction by two thirds is potentially of great importance. One model attempts to put this in clinical terms by transforming radiographic scores into estimates of irreversible physical disability, expressed as units from the health assessment questionnaire (HAQ) extrapolated over 10 years: thus for a 10 year period, the biologicals would prevent an increase in disability of 0.34 out of 3.0 (11.3%) irreversible HAQ units, over and above the clinical benefit from the improvement in the reversible components of the ACR 50.11 This exceeds the accepted level of minimal clinically important change of 0.22 HAQ units, though the model makes a number of simplifying assumptions.

## How safe are the new biologicals?

Our group also conducted a Cochrane review and network meta-analysis of 163 randomised controlled trials with 50 010 participants and 46 extension studies with 11 954 participants.10 This included data on biologicals from 63 (39%) of the trials and 18 (39%) of the extension studies in rheumatoid arthritis and from 100 trials and 28 extension studies of other conditions (ankylosing spondylitis, cancer, inflammatory bowel disease, psoriasis, and other similar conditions). The results did not differ substantively in the patients with rheumatoid arthritis compared with the others but provided more precise estimates.

Overall, compared with placebo, biologicals were associated with significantly higher rates of total adverse events, withdrawals because of adverse events, and reactivation of tuberculosis. After adjustment for dose, biologicals as a group were associated with an absolute 3% higher rate of withdrawals because of adverse events (number needed to harm 37; 95% confidence interval 19 to 190; fig 2 and the table) and an increased absolute 0.2% a year risk of reactivation of tuberculosis (681; 143 to 14 706); this estimate varies between countries where tuberculosis is endemic and those where it’s not, and probably between ethnic and social groups.

Fig 2 Comparison of each biological drug with placebo for harm (withdrawals because of adverse events)10

On limited data, we examined the previously reported possible adverse events of lymphoma12 and congestive heart failure13; these were not significantly different for biologicals and control treatment. However, biologicals are relatively new, and insufficient time has elapsed to enable detection of rare or delayed serious events associated with them. For example, several cases of progressive multifocal leukoencephalopathy (caused by the John Cunningham virus, which infects over 80% of humans) have been reported in patients treated with rituximab.14

## What are the precautions?

When considering treatment with a biological, precautions are necessary in patients with certain conditions (such as severe infections or risk factors for these) and after administration of certain live virus vaccines. Box 2 outlines these precautions in more detail.

#### Box 2 Precautions when prescribing biologicals

• Do not prescribe biologicals in patients with severe infections such as sepsis (to avoid the risk of worsening sepsis), abscess, active tuberculosis, opportunistic infections; moderate or severe (NYHA* class III and IV respectively) congestive heart failure (to avoid risk of worsening symptoms); or multiple sclerosis (to avoid risk of further demyelination)

• Identify for pretreatment counselling and infection reduction strategies those with:

• -Known risk factors for sepsis, such as neutropenia alone or in association with Felty’s syndrome

• -Coexistent diabetes

• -Bronchiectasis

• -Diverticular disease

• -Immunoglobulin deficiency

• Perform a tuberculin skin test or blood tests for tuberculosis, plus chest radiography if indicated—for example, if the skin test or blood test give equivocal or positive results

• Avoid starting biologicals within three months of administration of the following live virus vaccines:

• -BCG

• -Typhoid (oral)

• -Cholera (oral)

• -Measles

• -Mumps

• -Rubella

• -Oral poliomyelitis (Sabin)

• -Yellow fever

• -Varicella

• -Rotavirus

• -Japanese encephalitis (advised by the UK’s Department of Health)

• Check serology for hepatitis B before using rituximab (as fatal reactivation of previously quiescent virus can occur)

• Postpone the injection or infusion if the patient has a cold sore, has had a cold in the past week, or has unexplained new symptoms that might be an infection

• Discontinue biologicals for four weeks before surgery. Patients should not start or restart the biologicals until after their sutures or staples are removed and there is no sign of infection

• Warn patients that a rash, burning sensation, or itch may develop at the injection site, which may last 10 to 14 days without leaving a scar

• *The New York Heart Association’s functional classification system

## How are the new biologicals taken and monitored?

All biologicals are parenteral so far. Routes of administration can differ (such as intravenous infusion over two to three hours or subcutaneous injections that can be self administered), as can frequencies of doses (daily to every few months).

Monitor patients frequently initially, until the minimal target of remission or low disease activity is reached, and then no less often than every three to four months, with C reactive protein and key measures of disease activity and response (such as the disease activity score15 or the ACR 5016), as well as adverse effects.

Box 3 outlines in more detail how biologicals are taken and monitored.

#### Box 3 How are the new biologicals taken and monitored?

• Start treatment with methotrexate monotherapy or in combination with one or more other non-biological DMARDs (hydroxychloroquine, sulfasalazine, leflunomide) as soon as rheumatoid arthritis is diagnosed

• Aim to reach a minimal target of remission or low disease activity with treatment; if the target is not reached, adjust treatment every one to three months and monitor strictly (measure C reactive protein and disease activity score or equivalent, as well as monitoring adverse events)

• If the treatment target is not achieved with the first DMARD strategy, consider adding a biological DMARD when poor prognostic factors are present (such as the presence of autoantibodies, a high disease activity state, or early erosive disease); in the absence of poor prognostic factors, consider switching to another DMARD strategy. In the UK, NICE guidance recommends using a biological if two trials of six months of traditional DMARD therapy have failed to control symptoms or prevent disease progression

• When starting a biological, current practice would be to start with a tumour necrosis factor inhibitor (adalimumab, certolizumab, etanercept, golimumab, infliximab) combined with methotrexate

• Patients with rheumatoid arthritis for whom a first tumour necrosis factor inhibitor has failed should receive a different biological

## How cost effective are biologicals?

Biologicals are more expensive than traditional DMARDs. Two recent systematic reviews of studies of economic evaluations in rheumatoid arthritis found mixed results on the incremental cost effectiveness ratios. The systematic review for the European League Against Rheumatism’s guidelines found 25 published cost effectiveness studies, with costs ranging from $14 000 (£9000; €10 000) to over a million dollars per quality adjusted life year (QALY) gained.17 It concluded that if long term functional impairment and productivity losses are considered, then most estimates for the use of biologicals (in combination; after failure of traditional DMARDs; and others after failure of one tumour necrosis factor inhibitor) fall below the benchmark of$50 000 per QALY gained that many approval agencies use.

A similar systematic review over the same period but with slightly different criteria found 18 cost effectiveness analyses.18 Its more cautious conclusions were that at the threshold of \$50 000 per QALY gained, biologicals were not cost effective in patients who failed methotrexate combination therapy or sequential administration of DMARDs. Evidence of cost effectiveness in patients who failed methotrexate monotherapy may have been limited by the choice of comparator, methotrexate-resistant patients who continued to receive methotrexate.

Both reviews agreed that the most cost effective approach for managing rheumatoid arthritis seems to be to treat with a DMARD early in the course of the disease, to move through a sequence of other DMARDs, and if non-response continues, to add a biological. Many assumptions had to be made in coming to these conclusions because of lack of prospective data on long term responses to biologicals; the fact that different quality of life weights yield different cost effectiveness ratios; lack of consensus on the appropriate way to measure quality of life weights; and the lack of an agreed approach to determine the potential of biologicals to reduce downstream costs. Cost effectiveness may improve if the price of biologicals falls with the emergence of biosimilars (follow-on biologicals) and increasing competition.

## What might the future hold for the biologicals?

Different combinations of biologicals may achieve a more complete shutting down of the inflammation and joint damage; however, increased rates of infection have been seen with abatacept plus etanercept,19 and anakinra plus etanercept.20 Systemic inflammation is hypothesised to increase cardiovascular risk in patients with rheumatoid arthritis, and whether biologicals provide cardioprotection21 requires further study. We require long term data on benefits and safety of different biologicals. As few controlled trials can be continued ethically for more than one year, clinical epidemiologists and pharmacoepidemiologists need to agree on developing national and international registries that provide such data.22 23

## Our case scenario

The patient was given information on the biologicals, and a decision aid that provided the evidence and trade-offs and elucidated her preferences (http://musculoskeletal.cochrane.org/decision-aids). She elected to continue the methotrexate and start weekly subcutaneous etanercept injections. Six months later, her symptoms and function had improved and she was enjoying walking the dog again. No new erosions were visible on radiography.

#### Tips for patients

##### What is rheumatoid arthritis ?
• Rheumatoid arthritis causes your immune system to attack and inflame the lining of your joints. It often starts in the hands and feet: your joints become hot, swollen, stiff, and painful. Without treatment, inflammation permanently destroys the joints.

##### How is it treated?
• Early treatment with drugs such as methotrexate is important. If methotrexate (alone or in combination with other pills) is not controlling the inflammation, people are advised to take stronger, “biological” treatments as well such as etanercept (Enbrel). There are several different biological drugs, which all work by blocking cells and substances in the body that contribute to the inflammation.

##### What is it like to take biologicals?
• Some biologicals are given through a needle or tube inserted into your vein, in a clinic. Others are injected under the skin in different parts of your thigh or abdomen. A nurse or doctor teaches you how to do this. A family member or friend can also learn. You store the drug in a refrigerator and warm it to room temperature before use. Most people who fear self injection are able to give these injections with mild or no discomfort.

##### What are the benefits and harms of taking a biological drug?
• People who take a biological will have a better chance of a major improvement in pain, disability, and the number of tender and swollen joints than those who do not. People taking a biological are more likely to avoid serious joint damage. However, people who take a biological might get a rash, or burning, or itching at the injection site. This may last 10 to 14 days without leaving a scar. Rarely, a person may get tuberculosis from taking a biological. Before starting biologicals, a tuberculosis test is usually done. The drug is stopped if people develop a high fever or have an active infection and are taking an antibiotic.

##### Is there anything else I should know?
• Before starting treatment, you must tell your doctor about all the medications that you are taking and whether you have had any allergic reactions

• You should also let your doctor know if you have any infections, especially serious infections like tuberculosis. It is also important to tell your doctor if you have had cancer; are pregnant or breastfeeding; or are recovering from surgery or planning to have surgery

• People with multiple sclerosis and people with severe congestive heart failure should not take biologicals

• Decision aids on some biologicals are available at musculoskeletal.cochrane.org/decision-aids (where, under “Rheumatoid arthritis,” you will find Cochrane decision aids, through which you can discuss treatment options with your doctor). Click on, for example, “Should I take etanercept (Enbrel®) for rheumatoid arthritis?”

## Notes

Cite this as: BMJ 2011;343:d4027

## Footnotes

• This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Philip Routledge, professor of clinical pharmacology, Cardiff University. To suggest a topic for this series, please email us at practice{at}bmj.com.

• We thank Elizabeth Ghogomu, Lara Maxwell, Tamara Rader, Vivian Welch, Liz Lacasse, Jordi Pardo, Jack Karsh, Annette O’Connor, and Dawn Stacey for their contributions to this manuscript; Josef Smolen, Daniel Aletaha, and Edward Keystone for providing critical comments; and James O’Dell for providing information about ongoing clinical trial.

• Contributors: All authors contributed to the conception, implementation, and writing of this review, and all three led the two Cochrane systematic reviews on which this article is based. Elizabeth Ghogomu also contributed to the systematic review parts of this review. Tamara Rader, Jordi Pardo, Jack Karsh, and PT developed the decision aid that forms the basis for the “Tips for patients” box.

• Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work. PT received honorariums for quality of life consultancy with Bristol-Myers Squibb; chairs data safety monitoring boards for Chelsea Therapeutics and UCB, mandated for the Food and Drug Administration; is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives “arms length” funding from 36 companies; co-chaired an industry board of six companies (Abbott, Bristol-Myers Squibb, Merck, Roche, Schering Plough, UCB) for a biologicals registry of the Ontario Rheumatology Association, the Ontario Biologics Research Initiative (an arms-length registry that independently collects information, supported by a grant from the Canadian Institutes of Health Research (CIHR) matched by funding from these drug companies); and receives an honorarium from the CIHR grant. JAS has received speaker honorariums from Abbott, research and travel grants from Takeda, Savient, Wyeth, and Amgen, and consultant fees from URL Pharma, Takeda, Savient, and Novartis; he is a member of the executive of OMERACT. GAW received honorariums for consultancy with Novartis, Bristol-Myers Squibb, and Abbott; a grant from Bristol-Myers Squibb; and speaker honorariums from Abbott; he is a member of the executive of OMERACT and of the Scientific Committee for the Ontario Biologics Research Initiative.

• Provenance and peer review: Commissioned; externally peer reviewed.

• Patient consent not required (patient anonymised, dead, or hypothetical).

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