SARAA

The South African Arthritis and Rheumatism Association (SARAA) reference for
The use of biologic disease modifying anti-rheumatic drugs November 2011

Section A

Introduction:

The biologic disease modifying anti-rheumatic drugs (DMARDs) have been an important advance in the treatment of several rheumatic diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), undifferentiated spondylo arthritis, reactive arthritis, psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA) as well as some connective tissue diseases. Inflammatory arthritis not only cause damage to joints with resultant pain and loss of function, but are also associated with a significantly higher mortality. There is also a considerable social and financial impact with a large number of patients having to stop work as a result of their illness.

Early diagnosis and aggressive treatment has been shown to improve patient outcome. The goal for treatment of all diseases is clinical and radiologic remission using the treatment to target approach or tight control of disease activity. At present the biologic DMARDs are used after the failure of conventional therapy (methotrexate alone or in combination with other DMARDs) in appropriate doses. The use of a biologic DMARD is determined by the patient’s clinical factors and co-morbidities, identification of factors predictive of adverse prognosis, patient preference with regard to route of administration the registration information of the drugs and a knowledge of the possible risks of the biologic DMARDs. Once a patient has commenced therapy on a biologic DMARD, he or she should be monitored for clinical response at regular intervals and only continued if an adequate response is achieved and maintained. The use of sequential biologics may be necessary in patients who do not achieve or maintain this. It is not recommended to continue biologic therapy if the patient has failed treatment.

Use of the biologic DMARDs should only be initiated and followed up by rheumatologists experienced in the diagnosis, treatment and assessment of these patients and able to use the validated quantitative response measures for disease activity and functional disability.

These recommendations provide a guide, but the treatment needs to be tailored to the individual patient. The field of rheumatology is dynamic and data about biologic drugs is constantly being expanded. New data may become available after the current revision of the SARAA biologics reference that should be taken into account when using the drugs.

The TNF-a blockers are the biologics that have been used for the longest, but the newer biologics, rituximab, abatacept and tocilizumab have been clinically proven and SARAA welcomes the appropriate use of these biologics as indicated for the treatment of mainly rheumatoid arthritis either after TNF-a failure or synthetic DMARD failure.

The SARAA registry:
A registry was established by SARAA with the aim of capturing information about the use of the biologic DMARDs in South Africa with particular emphasis on the risk of and incidence of tuberculosis in patients on these drugs.

It is a pre-requisite for the use of and funding of biologics to submit demographic and clinical information to the SARAA registry. This is evaluated by the SARAA Registry Panel that consists of rheumatologists that voluntarily evaluate the applications so that the eligibility for use and on-going safety can be assessed. Applications must be approved or declined by at least 2 of the panel members. The registry panel can also make comments pertaining to an application. The identity of the patient and rheumatologist is not available to panel members.

Application process for a biologic DMARD in South Africa
3.1. Patient demographic and clinical information must be submitted to the SARAA biologics registry for all patients.
- Forms to be filled in for submission are available on the SARAA website. (www.SARAA.co.za ).
3.2. The prescribing of biologics is restricted to registered rheumatologists.
3.3. Testing for latent tuberculosis infection (LTBI) must be done prior to applying for a biologic and the results submitted. LTBI should be treated. The following results regarding testing for LTBI must accompany all new applications:
- Report of chest x-rays not older than 3 months at the time of the application.
- Results of tuberculosis Interferon Gamma Release Assays (IGRA) tests or tuberculin skin testing (TST).
3.4. Patients must sign an informed consent form to have information entered on the registry.
3.5. Clinical progress reports must be submitted to the registry yearly.
3.6. The registry should be notified of any adverse events or change in therapy.

General considerations with the use of biologic DMARD
4.1. Infection risk:
- The use of all biologic DMARDs is an increased risk of serious infection. The drugs should not be used if the patient has an active infection and should be discontinued if a serious infection occurs and only recommenced once the infection is clinically resolved.
- Biologic DMARDs should be used with caution in the following circumstances:
4.2. There may be an increased risk of peri-operative infections with patients on biologic drugs, although this is probably small. It is recommended that biologics are stopped at a time 3 – 5 times the half-life of the drugs and only restarted when there is good wound healing and no evidence of infection.
- The half-life of the biologic DMARDS:
4.3. Safety of biologic DMARD use in pregnancy has not been established.
- The TNF-a blocking drugs have been classed as category B drugs in pregnancy: No evidence of risk in humans. No definite harm to pregnancies could be ascribed to TNF-a blocking drugs in a review of 667 pregnancies. Ideally treatment should be stopped 3 months before planned pregnancy and recommenced after stopping lactation.
- Rituximab, Abatacept and tocilizumab are classed as category C drugs for use in pregnancy: “ no human studies or animal studies either show risk or are lacking. However potential benefits may justify potential risks.”
- Rituximab use may cause B-cell depletion in the foetus and it is recommended that the drug be discontinued a year before a planned pregnancy.
4.4. Vaccinations:
- Vaccinations against common infections, such as influenza and pneumococcal disease are recommended in patients on biologic DMARDs and can be given during the treatment, although the antibody response might be decreased. Vaccinations other than yearly ones, should be carried out before commencing biologic therapy.
- Vaccination with live, attenuated viruses (nasal influenza virus, herpes zoster and yellow fever) is contraindicated during biologic use. Patients needing to travel to countries where yellow fever is endemic may ask for a waiver for their travel documents if on a biologic drug.
4.5. Switching:
- When switching from one biologic DMARD to another, the new drug can be given when the next dose of the previous drug would have been given.
- With the use of Rituximab, it is recommended to initiate treatment:
- = 4 weeks after etanercept treatment
- = 8 weeks after infliximab of adalimumab treatment

Section B: Biologic DMARDs

The TNF-a blockers
- Currently available TNF-a blockers are infliximab (Revellex®), etanercept (Enbrel®) and adalimumab (Humira®). All of them block TNF-a and although there are differences in mechanism of action, pharmacokinetics and method of administration, the following will cover common attributes and differences shown in clinical studies.
- They are registered in South Africa as first line biologic drugs for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis in patients in patients with active, moderate to severe disease failing to respond to conventional therapy. See disease specific guidelines.
- Response to a TNF-a blocker can be seen by 2 – 4 weeks, with significant response by 12 – 24 weeks.
- Safety of the TNF-a blockers²:
- Autoimmune-like syndromes:
  - Autoantibody formation is common, but is usually not clinically significant. Drug induced lupus and anti-phospholipid antibody syndrome may occur.
- Cardiovascular:

Haematological:
- There have been reports of pancytopaenia and aplastic anaemia.

Liver function abnormalities:
- Modest ALT and AST elevations have been seen in patients on adalimumab and infliximab, usually not more than twice the upper limit of normal. Worsening of alcoholic hepatitis has been seen.

Infections:
- Tuberculosis (TB): Patients with immune mediated inflammatory diseases are at greater risk for the development of TB and those on TNF-a blockers can have a markedly increased risk. LTBI can be reactivated or the patient can develop a new infection. LTBI usually occurs in the first few months following the initiation of treatment while new infections can be seen at any time. About half of the infections will be extra-pulmonary. Infection risk can be minimised following the treatment of LTBI if present and routine follow up of all patients looking for signs of illness. Rates of TB reactivation have been higher in patients using adalimumab and infliximab. All patients should be monitored on an on-going basis for the development of TB and this should continue for at least 6 months after stopping treatment.
- Opportunistic infections: infections with fungi, listeria and non-tuberculous mycobacteria have been reported.
- Bacterial infections: Patients are at greater risk of serious infections requiring hospitalisation, although this is a small increase. The drug should not be administered if the patient has an active infection.
- Viral infections: Patients should be screened for viral hepatitis before starting a TNF-a blocker as reactivation of chronic infection can occur. If hepatitis B infection is found to occur during treatment, prophylactic antiviral treatment can be given.

Injection site reactions and infusion reactions:
- Injection site reactions are usually mild. Acute infusion reactions can occur with intravenous infliximab, but can usually be treated with corticosteroids and antihistamines and by slowing the infusion rate.

Malignancies:
- The risk of lymphoma and solid tumours does not seem to be increased, but there may be an increased risk of non-melanoma skin tumours.
- In patients with COPD, there may be an increased risk of lung cancer with TNF-a blocker treatment.
- An increased risk of malignancies was reported in JIA patients, but it is not known if the rate is increased compared to other patients with JIA.
- Anti-TNF therapy should be avoided in patients with a current or prior history

Neurological disease:
- There have been reports of rare cases of central and peripheral demyelinating syndromes including multiple sclerosis, optic neuritis and Guillain-Barré syndrome. These tend to occur within the first 5 – 8 months of use. Use of a TNF-a blocker is contraindicated if there is any history of demyelinating disease.

Male sexual function:
- Limited data, there has been no specific change in sperm volume and function. There have been reports of decreased sexual function.

Pulmonary disease:
- There have been cases of acute, severe interstitial lung disease, usually with pre-existing interstitial lung disease.

Skin disease:
- Several types of rash can develop, particularly psoriasis, but cases of Steven’s-Johnson syndrome, vasculitis and erythema multiforme as well as others have been reported. The skin reaction may subside with a switch from one TNF-a blocker to another.

Rituximab (MabThera®)
Rituximab is a chimeric anti-CD20 monoclonal antibody that depletes CD20 positive B-cells.
Use of rituximab is indicated for the treatment of moderate to severe, active RA following inadequate response to TNF-a blockers or in patients in whom the TNF-a blockers are contraindicated in patients failing conventional DMARD therapy.
It is given as 2 intravenous infusions of 500mg or 1000mg 14 days apart.
Co-medication of 125mg methylprednisolone is given with the infusions. paracetamol and antihistamine may also be given.
Rituximab is given in combination with weekly methotrexate, or if not tolerated, leflunomide.
The response to rituximab and protection from joint damage is greater in rheumatoid factor positive patients or anti-cyclic citrullinated peptide (ACPA) positive patients. In sero-negative patients an alternative treatment should be considered.
Time to response is usually by 8 – 16 weeks.
Retreatment is given to patients that have responded to treatment at 6 months or when the disease flares. Greater clinical efficacy was shown in patients treated at regular 6 monthly intervals compared to treatment on demand.
6.1. Adverse events
- Haematological side effects:
  - There have been reports on neutropaenia in oncology patients, but this seems to be rare in patients with autoimmune diseases.
- Infections:
  - There is a similar increase in the rate of serious infections compared to that seen with other biologic DMARDs. This is higher in patients with decreased IgG levels.
  - Tuberculosis:
    - There has been no increased incidence of TB reported on rituximab treatment, although there have been a few cases of TB reported in clinical trials.
  - Viral hepatitis:
    - Hepatitis B reactivation can occur. Screening for HBsAg and anti-HBc antibodies should be done in patients before treatment.
- Infusion reactions:
  - Infusion reactions occur most commonly with the first infusion. Pre-treatment with corticosteroids are given to reduce the incidence and severity of reactions.
- Malignancies:
  - There has been no evidence that rituximab is associated with an increased incidence of solid tumours or lymphoma.
- Neurologic syndromes:
  - Cases of progressive multifocal leucoencephalopathy have been seen in patients on rituximab.
- Skin reactions:
  - There have been reports of psoriasis and vasculitis on rituximab treatment.

Abatacept (Orentia®)
Abatacept is a fusion protein to CTLA-4 that acts as a T-cell co-stimulation modulator inhibiting T-cell stimulation.
It is indicated as a treatment for active, moderate to severe rheumatoid arthritis either after failure to respond to adequate treatment of chemical DMARDs or TNF-a blockers. It can be used as a monotherapy or in combination with chemical DMARDs.
The dose is 750mg or 1000mg every 4 weeks with a loading dose of 3 doses given at weeks 0, 2 and 4.
Response can be within 2 – 4 weeks, but most patients respond within 12 – 16 weeks.
7.1. Adverse events
- Infections:
  - As with the other biologic drugs, there is an increased rate of serious infection on abatacept.
  - Cases of TB were seen in clinical trial patients. The risk of reactivation on LTBI with abatacept is not known.
- Malignancies:
  - There has been no increased incidence in lymphoma or solid malignancies in patients with RA in clinical trials on abatacept or from registry data.
- Pulmonary disease:
  - An increased rate of serious lower respiratory tract infections was seen in patients with chronic obstructive pulmonary disease (COPD) and abatacept should be given with caution in these patients.
Tocilizumab (Actemra®)
Tocilizumab is a humanised anti-IL-6 receptor monoclonal antibody. It is administered as an intravenous infusion, given over 1 hour, every 4 weeks. The dose is 8mg/kg or 4mg/kg. The recommended dosage is 8 mg/kg. For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended. Tocilizumab is approved for the treatment of moderate to severe, active rheumatoid arthritis failing synthetic DMARDs or TNF-a blockers. Tocilizumab is used in the treatment of polyarticular and systemic JIA. Use with methotrexate is recommended, but it can be used as monotherapy.
8.1. Safety of tocilizumab
- Gastrointestinal
  - Gastrointestinal adverse events, including generalised peritonitis, lower gastrointestinal perforation, fistulae and intra-abdominal abscesses occurred with an incidence rate of 0,26/100 patient years in clinical trials with tocilizumab compared with placebo. It should be used with caution in patients with a history of intestinal ulceration and diverticulitis.
- Haematological
  - Neutopaenia was seen in clinical trials with decrease to < 1000 polimorphs per ml, rarely < 500/ml. This was usually transient and was not associated with an increased rate of infections.
- Infections
  - There was an increase in the rate of serious infections in clinical trials on tocilizumab compared to patients on placebo which was similar to the rates seen with other biologic DMARDs. The drug should not be when the patient has an active infection.
  - Tocilizumab decreases CRP levels through IL-6 inhibition and CRP levels may not increase as would normally be seen in an acute infection, limiting the use of CRP as a diagnostic indicator for infection.
  - Cases of TB and opportunistic infections have been reported in patients on tocilizumab and patients should be screened for latent TB infection before treatment.
  - Viral infections:
- Infusion reactions:
  - Serious infusion reactions to tocilizumab are uncommon, but can occur.
- Lipid levels:
  - Increases in plasma lipid levels are seen in 20 – 30% of patients and should be monitored and treated,
  - To date, an increase in cardiovascular incidents has not been seen in clinical trials.
- Liver enzyme and bilirubin elevations:
  - Liver enzyme elevations are seen in some patients on tocilizumab treatment. No incidences of hepatic failure have been documented, but dose reduction is recommended if on-going transaminase or bilirubin increase is found and liver function should be monitored regularly.
- Malignancies
  - There has been no increased incidence of malignancies in clinical trials on tocilizumab.
- Skin
- Erythroderma has been described related to tocilizumab.
Rheumatoid arthritis
9.1.Rheumatoid arthritis (RA) can be a devastating disease. Loss of function can occur early in the disease and after 10 years a third of patients have severe disability. About a third of patients will have to stop work due to their disease. There is an increased mortality, mainly due to co-morbidities associated with the disease. It is extremely important to make a diagnosis as soon as possible after the patient commences with symptoms and to start treatment with DMARDs. Signs of early RA may not be typical of established disease and patients with the following should be initiated on treatment: Swelling due to synovitis of 3 or more joints Tenderness when squeezed over the metacarpal phalangeal or metatarso phalangeal joints Marked morning stiffness

9.2 The diagnosis of RA is made on a combination of the clinical picture as well as serology and markers of inflammation. Classification criteria were updated in 2010 by the ACR and EULAR and new criteria were developed12.

9.3. Indicators of poor prognosis:
- Rheumatoid factor positive
- Antibodies to cyclic citrullinated peptides
- High markers of inflammation: ESR or CRP
- Development of erosions on x-rays within the first 2 years of disease.
9.4. Treat RA to target
- The target of treatment is remission or low disease activity as soon as possible. If this has not been reached, the patient should be re-evaluated and therapy adjusted every 1 – 3 months.
- This should be maintained throughout the course of the disease
9.5. Response criteria
- The Simplified Disease Activity Index (SDAI) is used in South Africa. This has been well validated and is a practical measure to assess disease activity10,11.
- SDAI = 26 represents high disease activity
- SDAI 11- 26 represents moderate disease activity
- The Stanford Health Assessment Questionnaire (HAQ) measures the level of a patient’s functional ability with a highest score of 3, where a patient is severely disabled.
9.6. Criteria for the use of biologic DMARDs
- Patients must have active rheumatoid arthritis
- All patients must have a history of use of at least 3 DMARDs used serially or in combination over a 6-month period at therapeutic doses or maximum tolerated doses.
- Methotrexate should be one of the DMARDs unless contra-indicated at a dose of preferably 20mg weekly.
- High disease activity: SDAI > 26 or
- Moderately active disease: SDAI score ³ 11 – 26 may be considered for biologic use if poor prognostic features are present.
- A letter of motivation should accompany any application for biologic use in a patient not fulfilling activity criteria.
9.7. Continuation of biologic treatment:
- It is recommended that treatment with a biologic DMARD should be continued only if there has been an adequate response to treatment following 6 months of continuous treatment.
- A patient failing treatment should be considered for a switch to another biologic or discontinuation of treatment.
- Adequate response to treatment is defined as:
- Improvement in SDAI score ³ 17 points from entry score after 6 months.
- Inadequate response:
- Failure to achieve a low disease state SDAI score £ 11 or a major SDAI response of ³ 17 points after 6 months of treatment.
- Response to treatment should be monitored at least every 6 months.
- An alternative biologic may be considered when treatment with a first biologic is withdrawn because of an adverse event before the initial 6-month assessment.
9.8. Biologics registered for use for RA
- Treatment with the TNF-a blockers, rituximab, abatacept and tocilizumab, in combination with methotrexate, have all been shown to be effective in the treatment of rheumatoid arthritis.
- Adalimumab, etanercept, abatacept and tocilizumab are approved as monotherapy for treatment of RA.
- The TNF-a blockers, abatacept and tocilizumab are all registered as drugs for first line treatment following failure of synthetic DMARD treatment.
- Rituximab is registered for second line treatment following TNF-a blocker failure, but in certain clinical situations, can be considered as first line treatment.
9.9. Clinical use of biologics in RA
- Increasing the dose or reducing the dosing interval of infliximab may provide increased benefit. Increasing the dose of etanercept has not shown increased benefit. No data is available on increasing the dose of adalimumab.
- There is no evidence that any one TNF-a blocker is more effective than another.
- Loss of response to a TNF-a blocker may occur.
- Failure on one TNF-a blocker does not preclude response to another, although if there was a primary failure to respond, there is less likelihood of response to a second one.
- The use of rituximab for treatment of RA is more effective in sero-positive patients.
- Response to rituximab is usually seen between 8 – 16 weeks.
9.10. Switching of biologics
- If a response is not achieved with one biologic, it is appropriate to switch to another.

Ankylosing spondylitis (AS)

10.1 Treatment with TNF-a blocking drugs (ASAS working group)¹⁴:

There is a diagnosis of definitive AS
There has been active disease for at least four weeks as defined by both a sustained Bath AS Disease Activity Index (BASDAI) of at least 4 and an expert opinion based on clinical features, acute phase reactants, and imaging modalities
Presence of refractory disease
Failure of at least two non-steroidal anti-inflammatory drugs during a single three month period
Failure of intra-articular steroids if indicated
Failure of sulfasalazine in patients with peripheral arthritis

10.2 Response to treatment

Assessment of response should be carried after 6 - 12 weeks of treatment. Rheumatologists are encouraged at each visit to record the (BASDAI), a Patient spinal (VAS) and AS physical measurements (occiput-wall, chest expansion, lateral spinal flexion and modified Schober test) to be able to form an opinion on whether treatment should be continued.
Response is defined as improvement of
at least 50% or 2 units (on a 0–10 scale) of the BASDAI

Psoriatic arthritis¹³

TNF-a blockers should be considered for the following patients:
- Patients with polyarthritis with at least 3 tender and 3 swollen joints who have failed treatment with at least 2 conventional DMARDs e.g. leflunomide, methotrexate or sulfasalazine, particularly where there is evidence of adverse prognostic factors: 5 or more swollen joints with elevated CRP persisting for more than 3 months, and/or structural joint damage due to disease, and/or previous use of oral corticosteroids.
- Severe persistent oligoarthritis that has a major demonstrable influence on well-being of the patient that has failed treatment with at least 2 conventional DMARDs and appropriate intra-articular therapy
- Anti-TNF therapy should be considered for those patients with active axial psoriatic disease according to the recommendation ankylosing spondylitis
- Treatment should be continued in patients who have responded after three months of treatment. In the case of non-responders, consideration should be given to a further 12 weeks of therapy if there has been a partial response and then continuing therapy if there has been a full response compared to baseline. A partial response is defined by some improvement in swollen and tender joint score and no worsening in physician or patient global score.
- In the case of failure of an anti-TNF therapy, either due to inefficacy or toxicity, an alternative anti-TNF therapy should be considered

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