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Rheumatoid Arthritis


Module III

Management: Biological disease modifying anti-rheumatic drugs,
glucocorticoids and special situations (pregnancy & lactation)














Dr Ved Chaturvedi MD, DM
Senior Consultant Rheumatologist, Army Medical Corps
President, Indian Rheumatology Association

Dr Vinod Ravindran MD, FRCP
Assistant Professor of Rheumatology
MES Medical College, Perinthalmanna, Kerala

Dr Molly Thabah MD
Assistant Professor of Medicine
JIPMER, Puduchrery









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BIOLOGIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
Since the late 1990s, increasing emphasis has been placed on the use of biologic agents
combined with small molecule agents such as MTX. These combinations have proved
effective in the treatment of patients with severe or long-standing disease and have proved
their ability to slow or prevent radiographic progression of disease. As a class, the most
effective of biologic approaches to date has been the combination of TNF antagonists (e.g.,
adalimumab, etanercept, and infliximab) with MTX. In refractory disease, the addition of
adalimumab, etanercept, or infliximab to MTX treatment provides additional benefit to
patients with persistent active disease.

With all three of the available TNF inhibitors, trials have shown that more than 50% to 70%
of the patients had at least a 20% response, and more than 40% of patients had a 50%
improvement, as measured by the ACR criteria. Although each of the cohorts studied in these
trials was slightly different, no significant side effects were apparent in the combination arms
above and beyond what was seen in the MTX-only arms of the studies, suggesting a good
safety profile and strong benefit-to-risk ratio when put into perspective with the relative
severity of the disease. Beyond the TNF inhibitors, there are increasing data that biologic
agents such as abatacept and RTX can work effectively even in patients who have failed TNF
inhibitors, continuing to provide disease control in patients with the most refractory disease.

INHIBITION BY TUMOR NECROSIS FACTORS
The TNF- has a pivotal role in initiation and perpetuation of the inflammatory and
proliferative processes of rheumatoid synovitis. As a class, the TNF inhibitors (adalimumab,
etanercept, and infliximab) seem to be one of the most effective means of improving
symptoms and signs of disease, increasing function, and reducing structural progression of
RA. In the absence of truly useful biomarkers or surrogates to distinguish patients likely to
respond to therapy from patients who would not respond, it is reasonable to suggest that most
patients should be treated with MTX before advancing to a TNF inhibitor. Should a patient
fail to achieve a significant response to MTX over a few months, however, switching the
patient to a TNF inhibitor as monotherapy or adding a TNF inhibitor and treating in
combination with background DMARDs should be considered.



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Etanercept
Etanercept was the first TNF- inhibitor to be approved by the U.S. Food and Drug
Administration (FDA) for use in RA. It is a fusion protein of the soluble portion of the human
TNF p75 chain of the receptor and the fragment crystallizable (Fc) portion of human IgG1.
The receptor portion binds extracellular TNF-, effectively neutralizing it, and the Fc moiety
prolongs its circulating half-life. This drug is administered as a subcutaneous injection of 25
mg twice weekly or a single 50-mg injection once a week.

Infliximab
Infliximab is a chimeric monoclonal antibody against TNF. It was the second anti-TNF agent
approved for use by the FDA in treatment of RA and had previously been approved for use in
Crohn's disease. Most of the antibody is human; however, a small portion of the Fab region is
murine in origin. The antibody is given via intravenous infusions of 3 to 10 mg/kg. The
recommended dosing regimen is 3 mg/kg with infusions at weeks 0, 2, and 6, and every 8
weeks thereafter. If patients fail to achieve a significant benefit, the dose can be increased, or
the dosing interval can be shortened. For pharmacokinetic and pharmacoeconomic reasons, it
may be more desirable to shorten the dosing interval rather than to increase the dose.
Concomitant administration of MTX gives more sustained benefit, may reduce the clearance
of the drug, and possibly may lead to less immunogenicity, reflected by a reduction in human
antichimeric antibody formation. Whether concomitant use of other small molecules affords
the same advantage is unknown, but plausible.

Adalimumab
Adalimumab is the third biologic agent directed against TNF for the treatment of RA.
Adalimumab is a fully human monoclonal antibody directed against TNF and is delivered as
a subcutaneous injection once every other week, or, in patients with insufficient response, it
can be given once a week. Use of background MTX with this agent also seems to increase the
duration of response, possibly by slowing the clearance of the drug. As was shown with
etanercept and infliximab, adalimumab showed significant benefits when combined with
MTX.

Adverse events with anti-TNF therapy
Serious Infections (Excluding Tuberculosis)
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When TNF inhibitors were first introduced in the late 1990s, there was concern that blocking
TNF might impair the host defense system. Clinicians have since been reassured that, in
general, there have not been significant problems with serious bacterial infections for most
patients treated with TNF inhibitors. Occasional patients taking etanercept, infliximab, or
adalimumab have developed serious bacterial infections or opportunistic infection, however.
Predicting which patients will develop an infection is almost impossible. A degree of
vigilance and the recognition that infections can occur should be part of all treatment
initiation and monitoring efforts. In addition, it is apparent that in debilitated patients (e.g.,
patients with infections such as skin ulcers or pneumonia or patients with other illnesses that
would increase the risk of infection or diminished immune surveillance) TNF inhibition
should be used with caution.

Tuberculosis
Reactivation of tuberculosis has been reported with all the TNF inhibitors. There seem to be
more reports with infliximab than with etanercept or adalimumab. Researchers are unclear as
to whether these differences are related to differing mechanism of action, structure,
pharmacokinetics, route of administration, or the patient populations studied. Given the
potential for reactivation of tuberculosis, appropriate screening should be done before the
initiation of treatment with a TNF inhibitor.
Malignancies
RA conveys an increased risk for the development of lymphoproliferative disease. The
development of lymphoma has been reported with each of the TNF inhibitors. It is unclear,
however, whether this development is related to the medication itself or the underlying
disease.
Demyelination
Rare cases of multiple sclerosis, optic neuritis, and demyelination have been reported in
patients taking TNF inhibitors. These cases have been sporadic and seem mostly to resolve
when the TNF inhibitor is withdrawn. Because demyelination is a rare occurrence in the
population at large, it is unclear whether these events are occurring more often than expected.
It is recommended that TNF inhibition be avoided in patients with a history of demyelinating
illness or who have features of unique neurologic problems.
Congestive Heart Failure
In patients with known congestive heart failure, TNF inhibitors should be used with caution
because they may worsen cardiac function.
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IL-1 antagonist
IL-1, similar to TNF-, has been implicated in the pathogenesis of RA. It is produced by
rheumatoid synovium and other tissues, predominantly by macrophages. There is, however, a
circulating protein found in extracellular tissues, IL-1 receptor antagonist, which is a
biologically important protein that functions as a naturally occurring antagonist to IL-1. A
recombinant human form, anakinra, has been developed. It is given as a daily subcutaneous
injection of 100 mg.

Generally, anakinra has been shown to be safe and well tolerated. The most frequent side
effect has been injection site reactions, which occur in more than 50% of the patients who
take this medication. Although mild and self-limited, this side effect can be very
uncomfortable. Anakinra is an infrequently used agent for the treatment of RA and is often
reserved for patients who have failed other agents or may be inappropriate candidates for
TNF inhibition. This restriction of use is partially related to its cost, the need for daily
subcutaneous injections, and the perception of being less effective as a therapeutic biologic
compound than are the TNF inhibitors.

Abatacept
Abatacept is a soluble, recombinant fusion protein that is composed of the extracellular
domain of cytotoxic T lymphocyteassociated antigen-4 (CTLA-4) and the modified Fc
portion of IgG1. It seems to be effective in the treatment of RA by selectively modulating the
CD80 or CD86/CD28 costimulatory signal required for full T cell activation. T cells normally
require two signals for full activation. The first signal is the antigen expressed in the context
of the major histocompatibility complex (MHC) binding to the T cell receptor. The second
signal is a costimulatory signal. One important costimulatory pathway is the engagement of
CD80/CD86 on the surface of an antigen-presenting cell with CD28 on the T cell, facilitating
T cell activation. In the normal sequence of events, the naturally occurring inhibitory
molecule CTLA-4 is induced on the surface of the T cell downregulating the CD28-mediated
T cell activation. CTLA-4 has a markedly greater affinity for CD80 or CD86 than does
CD28, out-competing CD28 for CD80 or CD86 binding. Abatacept, similar to CTLA-4,
competes with CD28 for CD80 and CD86 binding and can be used to modulate T cell
activation selectively.

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Clinical trials have shown the efficacy of abatacept in the treatment of RA. Abatacept is
administered as a 30-minute infusion days 1, 15, and 30, and monthly thereafter.

Rituximab
RTX is a chimeric monoclonal antibody targeting CD20
+
B cells. Clinical trials using RTX
have shown efficacy and safety in treating RA and have provided further evidence for the
role of B cells in the pathogenesis of the disease. CD20 is a target for B celldepleting
therapy because it is uniformly expressed on B cells, but not on stem cells or plasma cells.
By binding CD20, RTX depletes peripheral B cells through several postulated mechanisms,
including cell-mediated and complement-dependent cytotoxicity and promotion of apoptosis.

GLUCOCORTICOIDS

Glucocorticoids (GCs); also called corticosteroids or more loosely, steroids are used widely
in the management of RA (BOX 1). In some situations there timely usage could be life
saving. However their indiscriminate usage could lead to several undesirable side effects.
Some of the common side effects of steroid usages are weight gain, facial odema, easy
bruising, glaucoma, cataracts, hypertension, diabetes, atherosclerosis, psychosis, infections,
delayed wound healing. The adverse effects of steroid therapy therefore should be considered
and discussed with the patient before the therapy is started.

Initial dose, dose reduction and long-term dosing depend on the underlying rheumatic
disease, disease activity, risk factors and individual responsiveness of the patient. When it is
decided to start steroid treatment, comorbidities and risk factors for adverse effects should be
evaluated and treated where indicated; these include hypertension, diabetes, peptic ulcer,
recent fractures, and presence of cataract or glaucoma, presence of (chronic) infections,
dyslipidaemia and co-medication with non-steroidal anti-inflammatory drugs.

For prolonged treatment, the steroid dosage should be kept to a minimum. During treatment,
patients should be monitored for body weight, blood pressure, peripheral oedema, cardiac
insufficiency, serum lipids, blood and/or urine glucose and ocular pressure depending on
individual patients risk, GC dose and duration.


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MEDICINES USE FOR RA DURING PREGANANCY AND LACTATION

As several rheumatic diseases affect the women of child bearing age group pregnancy and
lactation poses special challenges. When treating women of childbearing age with chronic
medications, it is imperative that the potential effects of medication use on the developing
foetus are considered, whether a future pregnancy is planned or an unanticipated pregnancy is
discovered. The goals of treatment are to control maternal disease activity while
simultaneously maximizing the potential for a safe and successful outcome for the foetus.
Methotreaxate should be discontinued at least 3 months prior to conception. If a woman
treated with leflunomide wants to become pregnant, the medication should be stopped and
cholestyramine should be administered in order to rapidly decrease the blood levels to the
acceptable level. Hydroxycholoquine, azathioprine, steroids and sulphasalazine are some
drugs which can be used safely when trying to conceive.

Sulfasalazine use can lead to reduced fertility in men owing to oligospermia and reduced
sperm motility. Fortunately, this is not an irreversible event; spermatogenesis should return to
normal approximately 2 months after cessation of the drug. Men wishing to conceive a child
with a partner should be counselled to discontinue the medication 3 months prior to
conception.

Table 1 lists safety of commonly used drugs for RA in pregnancy and lactation. When
counselling women with autoimmune diseases regarding medication use during pregnancy, it
is important to balance the potential adverse effects of medication use with the potential
adverse effects of untreated, active disease during pregnancy.










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Box 1: Indications for the possible use of glucocorticoids in RA

Bridge therapy for patients who have experienced a severe functional decline
with limitations interfering with necessary daily living or vocational
activities.
Patients with NSAID contraindication who have acute inflammation unlikely
to respond rapidly enough to second line agents.
Rheumatoid vasculitis or other serious life threatening or organ damaging
manifestation.
Men or women not at reduced risk of bone loss, for whom GCs may be
reasonable in combination therapy regimens with a single daily dose of
less than 7.5mg/day.
Pregnant or lactating women with active RA.
























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Table 1: Safety of drugs used in rheumatology in pregnancy and lactation
Drugs Safe in pregnancy Safe in lactation
Paracetamol Yes Yes
NSAIDS Yes (until 32 weeks) Yes
COX-II inhibitors No Not known
Steroids* Yes Yes
Hydroxychlolroquine Yes Yes
Sulphasalazine Yes Yes
Methotrexate No No
Leflunomide No No
Azathoprine Yes Yes
Calcium and vitamin D Yes Yes
Bisphosphonates No No
*Prednisolone, methyprednisolone, dexamahasone, betamethasone- all to be used in the
lowest possible doses.