Treating Rhaumatoid Arthritis (RA)
and Ankylosing Spondylitis(AS) with Special Drugs:
An Overview of Newer Drugs A NEW ERA OF TARGET THERAPY

by Dr Arvind Chopra, MD, DNB, Director and Chief Rheumatologist, and Dr Kiran Adam

SUMMARY POINTS:

Note: Treatment of RA and AS begin with providing relief of pain using analgesics and non-steroidal anti-inflammatory drug (NSAID). However, there are several other targets like inflammation swelling of joints, control of immune mediated inflammatory process, osteoporosis, anemia, poor health, preventing joint deformities and disability. RA is a systemic disease and can effect several other organs. It reduces quality of life and life span. It makes patients more prone for infections and certain cancers. There is an important role of physiotherapy, exercise and proper body weight. It is also necessary to maintain good mental health. Patients must look after their nutrition and life styles. Tobacco is a major risk factor and must be avoided. However, in this article, we focus on the special drugs used to treat RA and AS.

• DMARDs (diseasemodifyinganti rheumatic drugs) are special drugs that act on the immune system to reduce the signs and symptoms and bone damage and other systemic complications of autoimmune inflammatory arthritis disorders like rheumatoid arthritis and ankylosing spondylitis
• DMARDs unlike pain killers (Crocin™), steroids (wysolone™) and anti-inflammatory drugs (like Voveran™ and Naprosyn™ ) are slow acting and may take several weeks to months to show optimum effect.
• Over time, long term use of DMARDs leads to good control of disease with reduction in requirement of pain killers, steroids and antiinflammatory drugs.
• DMARDs are prescribed by specialists like rheumatologists and need careful supervision and repeated monitoring (including blood tests) to check for efficacy and drug related side effects.
• Blood cells and hemoglobin, and functions of liver and kidney need to be carefully monitored and care needed to avoid infections; uncommonly skin reactions and gut related effects may be seen.
• Traditional DMARD include methotrexate, hydrox ychloroquin, sulfasalazine and leflunomide and are most useful in RA.
• The efficacy of oral DMARD is much less in AS.
• In recent times, biological DMARDs with very specific and potent therapeutic effect on some important component of the immune system have been introduced to treat several types of bad severe arthritis.
• Biologic DMARD are very effective in the management of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and several other inflammatory arthritis and can produce complete control/remission in several patients
• They target specific components (such as cytokines, cells, and receptors) of the body's immune system that are responsible for the severity and complications.
• Biologic DMARDs control the symptoms rapidly and the effect can be very dramatic.
• The decision to start biologic DMARD is taken with utmost care by the rheumatologist after detail evaluationof several clinical , investigation and socioeconomic factors
• RA and similar inflammatory arthritis are lifelong disorders and need long term medication and therefore the rheumatologist will carefully decide how long to take biologic DMARD as per an individual case.
• Biologic DMARD can be used for a short course to quickly control the disease flare and severity but this needs expert handling by the rheumatologist.
• Single or few injections for just symptomatic relief are not recommended.
• Patients on biologic DMARD may also require several other medicines (such as analgesics, anti-inflammatory (NSAIDs) , immunosuppressive, conventional DMARD, iron-calcium supplements etc) but the need becomes lesser in time as arthritis improves
• All patients on Biologic DMARD are closely monitored to ensure improvement and detect any early drug toxicity; repeated laboratory blood tests are required
• All patients selected for or on biologics should be advised on suitable immunization/ vaccination schedule. Patients may be considered for protection against influenza and other lung infections
• Biologic DMARD are not pain killers but through superior disease control often reduce the requirement of analgesics and steroids; the requirement may become nil
• Biologic DMARDs increase the risk for infections including tuberculosis.
• Compared to routine DMARD and steroids, biologic DMARDs are much more safer; side effects connected with gut, liver, lungs and heart are uncommon
• Biologic DMARD, especially if begun early, effectively prevent or at least reduce the chances of several bad complications of rheumatoid arthritis and other inflammatory arthritis such as joint deformities, osteoporosis, and ischemic cardiac and blood circulation disorders
• Biologic DMARDs are shown to improve quality of life and longevity.
• Only rheumatologists are authorized to prescribe and use biologic DMARD

SCREENING

It is essential to screen patients requiring DMARDs and in particular Biologic agents for general health blood hemogram & cell count and normal kidney and liver functions and to exclude any infection or even its carrier state. Some biologics like anti tumor necrosis factor agent carry a higher risk for infections. Biologic DMARD should not be given to patients with severe heart and/or lung problems. Several good studies show that overall biologic DMARDs do not increase the risk for cancer. Biologics are not advised to be given during pregnancy and lactation.

Some of the screening tests required are – blood tests fpr hepatitis B and hepatitis C, and human immunodeficiency virus (HIV), blood test for tuberculosis active or latent (TB GOLD Quantiferon), skin test for TB (,Mantaux Test),Sonography of abdomen and pelvis and Chest Xray. In case of doubt of TB, CT scan may be required.

BIOSIMILARS

Biologic DMARDs are expensive . Pharmaceutical companies manufacturing biologic agents have several patent rights and protection which are limited by a certain period mostly 10-12 years. It is very difficult to copy the formula of biologic drugs. However, once the patent expires, other companies can undertake special research to create similar version of biologics called 'biosimilars'.To ensure high standard of quality and safety, biosimilars are manufactured under tight regulations and have to be approved by a special system. In India, these rules are made and supervised by the Drug Controlled of India. The main advantage of biosimilar is that of price- it costs less and that increases the affordability. Generally, biosimilars are thought to cost 30% less than the original biologic agents. Biosimilars of Infliximab( trade name Infimab ) , etanercept (tradename Etacept,Intacept), adalimumab(trade name Exemptia) and Rituximab(Trade name Reditux RA,Mabtas RA, Tortiz RA) are now available in India are likely to cost less than original Biologic drugs. Several other biosimilar DMARD in india are in pipeline to be launched in hear future.Though the original biologic agent of Adalimumab named Humira is not available in India, several biosimilars are being marketed for this agent (Exemptia).It should also be noted that consistent with the socioeconomic burden in our community especially for patients of arthritis, several companies of original Biologics and Biosimilars Annonuce special Concessional schemes from time to time.

We have included the mention of Itolizumab in the table because it has shown promising results in patients of RA in Indian drug trials. However as of now it is approved for use in skin psoriasis.It is still under clinical development by Biocon, Bangalore for other arthritis disorders.

Biologic DMARD	Trade Name	Target	App Cost per unit	Indications	Usuals Single Dose for adults 60kg	Initial Regimen#
Infliximab	Remicade	TNF	Rs 32,000/=per 100 gm via(as per 4 months course)	RA, JIA, AS, SSA, Psoriasis Arthritis, Inflammatory COlitis-Arthritis	200-300 mg infused intravenously every 4-6 weeks	3-4 doses over 12-20 weeks
Etanercept	Enbrel	TNF	Rs 14,000/=per 50 gm vial	RA, JIA, AS, SSA, Psoriasis	50 mg injection subcutaneous weekly	12-16 weeks
Rituximab	Mabthera, (Ristova)	B cell	Rs 28,000/= per 500 gm vial	RA	1 gm start and repeat after 2 weeks; given as intravenous infusion	Give once in 6 months to one year
Tocilizumab	Actemra	IL-6	Rs 15,000/= for 200 mg vial	RA, JIA	8 mg/kg Body wt; intravenous infusion monthly	At least 4-6 doses over 4-6 months
Abatacept	Orencia	T cell	Rs 22,500/= for 250 mg vial	RA, JIA, AS, SSA, Psoriasis	750 mg intravenous infusion every 2-4 weeks	3-4 doses over 12 weeks
Itolizumab	Alzumab	CD 6	Rs 7000/= for 25 mg vial	Psoriasis arthritis, RA(under evalution)	1.6 mg/kg body wt intraveneous infusions infused every monthly	twice monthly infusion for 3 months and then monthly for 6 months
Note: The above is an outline and rheumatologist needs to be consulted prior to prescribing biologic DMARD. See text for abbreviations; RA: rheumatoid arthritis; JIA: juvenile idiopathic arthritis; AS: ankylosing spondylitis; SSA: seronegative spondyloarthritis; # the duration of the initial regimen use has been empirically worked out in Center for Rheumatic Diseases, Pune to control the intensity of the disease in a socioencomical and scientific manner; however the patients will continue to use oral traditional DMARD for long term control NOTE: the dose of biologic agent shown above is usually used to treat RA and may differs in other forms of arthritis