Abstract:

Rheumatoid arthritis (RA) is the commonest cause of chronic inflammatory arthritis all over the world including India.The clinical course of rheumatoid arthritis is highly variable, spontaneous disease fluctuations are common. The treatment of RA is a real challenge. The effective management of patients with RA involves a multidisciplinary approach which endeavours to deal with functional psychosocial as well as physical problems. The aims of treatment include relief of pain, reduction of inflammation, functional improvement, control of disease activity and prevention of deformities.

Keywords: Rheumatoid Arthritis, Inflammation, Treatment,Combination Therapy

Introduction
Rheumatoid arthritis (RA) is the commonest cause of chronic inflammatory arthritis all over the world including India. The over all prevalence of the disease is around 1% in the general population[1]. Although RA is considered as a disease of the joint it is important to recognize that it can exhibit a variety of extra articular manifestation which clearly indicates that this illness has features of a systemic disease and is capable of involving a variety of major organ systems. The clinical course of rheumatoid arthritis is highly variable, spontaneous disease fluctuations are common. A small percentage of patients go into remission, generally within two years of disease onset. Most patients will have a progressive course with variable disease activity eventually leading to considerable functional disability[2]. 

The treatment of RA is a real challenge. The effective management of patients with RA involves a multidisciplinary approach which endeavours to deal with functional psychosocial as well as physical problems. The aims of treatment include relief of pain, reduction of inflammation, functional improvement, control of disease activity and prevention of deformities.
General measures 

Patient education 
It has an important role in the long term management of RA. It provides information on the disease and its therapies which gives the patient a realistic outlook regarding the disease and allows them to be involved in the therapeutic decisions.

Diet and exercise
No specific dietary modifications are found to be useful in the management of rheumatoid arthritis. However addition of fish oil or fish supplements which are rich in omega 3 fatty acid are found to reduce the inflammation in the joints. The omega 3 fatty acids compete with arachidonic acid for the lipoxygenase enzyme resulting in decreased production of leukotriens with pro inflammatory properties[3]. Studies shows that fish oil supplementation has enabled reduction or even discontinuation of nonsteroidal anti inflammatory drugs in some of the patients with RA[4,5].
It is also important that all patients with RA regularity perform a general exercise programme to improve and maintain general fitness and maintain muscle bulk around the joints. 


Physiotherapy 
Physical modalities are a useful adjuvant in the management of patients with RA.In acute phase appropriate positioning of the joints, splinting to prevent the deformities and maintenance exercises of the other muscle are needed. Cryotherapy is also useful to reduce the pain in acutely inflamed joints. In chronic phase active isotonic (dynamic) exercises, and stretching exercises are useful. Specific physiotherapeutic modalities were ultrasonics, application of heat by wax bath or hydrotherapy which can reduce the swelling and stiffness of the chronically inflamed joints. 

Pharmacotherapy
The major aims of pharmacotherapy in RA are symptom relief as well as to achieve sustained disease remission. The major groups of drugs used are nonsteroidal anti inflammatory drugs (NSADIS) disease modifying antirheumatic drugs (DMARDs) corticosteroids and biological agents.

Nonsteroidal Antiinflammatory Drugs (NSAIDs)
The father of Modern Medicine Hippocrates relieve the pain of his arthritis patients with willow leaf tea in 400 BC. Since the introduction of Willow bark by Edward Stone in 1763 for rheumatic fever, many patients with rheumatoid arthritis were also treated with similar way. The active ingredient of willow bark, Salicilin was extracted by Leroux in 1829. In 1853 Felix Hoffman developed a process to synthesize Acetyl Salicylic Acid (Aspirin). The wide spread use of Aspirin as an anti-inflammatory agent started by Dresser in 1899[6]. More than 100 years after its introduction aspirin is a very effective drug in the management of rheumatoid arthritis. The dose required in acute arthritis is 90-120mg/kg/day. Many patients develop severe gastrointestinal upset at this dose of 4-6gm/day.The term NSAID was first applied to phenylbutazone which was introduced into clinical practice in 1949 soon after the introduction of steroids[7]. In 1963 another NSAID indomethacin has been introduced. Since then a variety of NSAIDs came to the market and many of them stood the test of time in spite of various side effects.
In 1982 Sir John Vane won the Nobel prize for discovering the mechanism of action of Aspirin and other NSAIDs. He proved that these group of drugs in spite of their diversity in the chemical structure, act by inhibiting the cycloxygenase (COX) enzyme leading to inhibition of prostaglandins. In the last decade of 20th century, Needleman and colleagues discovered two isoenzymes of cycloxygenase- COX-1 and COX-2.The COX-1 is a house keeping enzyme which is concerned with production of prostaglandins which are protective to stomach and kidney and the COX-2 is concerned with inflammation. This has led to the discovery of partially and highly selective COX-2 inhibitors. Even though highly selective COX-2 inhibitors have markedly reduced the gastrointestinal side effects, the renal and other side effects remains the same. More over the highly selective COX-2 inhibitors are devoid of anti platelet action and has pro thrombotic tendency in susceptible population. 

Classification of NSAIDS
Chemical classification

1. Salicylates :Aspirin
2. Indoles : Indomethacin
3. Pyrazoles : Phenyl Butazone
4. Fenamate: Mefenamic acid
5. Propionic acid: Ibuprofen, Ketoprofen, Flurbiprofen, Naproxen
6. Phenyl acetic acid : Diclofenac, Aceclofenac
7. Oxicam : Piroxicam, Tenoxicam, Meloxicam
8. Sulphonanilide : Nimesulide
9. Coxibs:Celecoxib,Rofecoxib,Valdecoxib,Parecoxib,
Etoricoxib,Lumiracoxib



Classification based on COX selectivity 

1. Non COX selective NSAIDS
Aspirin, Indomethacin Diclofenac, Piroxicam, Ibuprofen
Naproxen, Mefenamic acid
2. Preferential Cox 2 inhibitors
Nimensulide, Meloxicam, Nabumetone,Aceclofenac
3. Highly selective Cox-2 inhibitors
1st generation: Celecoxib,Rofecoxib
2nd generation : Valdecoxib Parecoxib, Etoricoxib, Lumira coxib


Choice of NSAIDs

As there are lot of NSAIDs available the choice depend on the efficacy toxicity ,availability and cost 

Disease modifying Anti Rheumatic Drugs (DMARDs)
This group of drugs can suppress the disease activity effectively and will prevent the progression of cartilage and bone degradation and also cause functional improvement. These drugs starts the action slowly but the potential importance of treating RA with DMARDs in its earliest stage is increasingly recognized in the recent years. Early suppression of synovial inflammation can arrest or retard the progressive irreversible joint damage. Now a days these drugs are started along with NSAIDS if the arthritis persist for more than three months and continued at the lowest dose for 2 to 5 years or even longer after disease remission. Periodic assessment of the disease activity and clinical examination and investigations to monitor the toxicity are highly essential when the patient is put on DMARDs.

Antimalarials
Chloroquine and hydroxy chloroquine are two antimalarial drugs that have been used as DMARDs in the treatment of RA since early 1950s[8]. These drugs act by stabilizing the lysosomal membrane and inhibiting the metabolism of deoxy ribonucleotides.
These anti malarials are relatively weak drugs and are useful in early mild RA or as adjuvant to other DMARDs. As they are cheap and less toxic often considered as initial DMARD in mild cases. The major toxicity is retinopathy and needs baseline and periodic ophthalmic check up (once in 6 months for chloroquine and once in an year for hydroxy choloroquine). The incidence of chloroquine retinopathy is low in Indian population. Chloroquine is given at a dose of 250mg daily and Hydroxy chloroquine 200 - 400mg daily.
Sulphasalazine
Unlike most of the currently used DMARDs, Sulfasalazine was developed specifically for the treatment of Rheumatoid arthritis. Following the discovery of sulphonamides as antibacterial agents they were used in numerous non bacterial inflammatory disease with little success. In the late 1930s Nana Svartz designed a compound that contained both a salicylate and a sulfa component and in early 1942 reported its positive therapeutic benefits in RA[9].


The mechanism of action sulphasalazine in RA is still remain undefined. The mechanism could be multifaceted like inhibition of folate metabolism, alteration in bowel flora, reduction in immunoglobulin level and diverse actions on prostaglandin metabolism. The usual starting dose is 500mg daily to be increased by 500mg weekly increments to a dose of 2 to 3 gms/day. The common side effects are leucopenia thrombocytopenia and hepatotoxicity. Periodic check up of blood counts and serum transaminase levels are necessary to monitor these side effects.

Methotrexate
Over the last 10-15 years methotrexate has become the most popular DMARD in the treatment of Rheumatoid arthritis. The drug was developed as antimalignant drug by an Indian doctor Yellapragada Subbaraw in 1948 which act by inhibiting the folic acid metabolism. In 1951 inspite of its introduction in the treatment of dermatomyositis by another Indian doctor Malaviya[10] and the wide spread use for psoriasis by dermatologists, methotrexate was not a popular DMARD for RA until 1980s. But today methotrexate is the most widely used DMARD all over the world including North America.


Methotrexate inhibits dihydrofolate reductase enzyme and thereby prevents the proliferation of immune cells. There are two biochemical mechanisms by which methotrexate may modulate inflammation. They are promotion of adenosine release and inhibition of pathologic transmethylation reactions[11]. Adenosine has potent anti inflammatory actions. It also directly inhibit the cellular response of interleukin-1.
The dose of methotrexate is 7.5 to 15mg weekly orally or parentally (subcutaneous or intramuscular) Folic acid supplementation is found to reduce the side effects without compromising the efficacy. The side effects are gastrointestinal, bone marrow suppression, hepatotoxicity and hypersensitivity pneumonitis which are extremely rare in the above low weekly doses. In spite of the internal concerns about it long term toxicity it is now clear that the long term 'side effects' of Rheumatoid arthritis are much worse than those related to administration of methotrexate. Before starting methotrexate complete blood counts including platelets, pre-treatment liver function test, hepatitis B and C serologies, and a chest radiograph should be done and while on the drug monitor the leucocyte and platelet count, transminase, creatinine and serum albumin every 4- 8 weeks interval. 

Leflunomide 
Leflunomide is an isoxazole derivative with disease modifying and immunomodulatory properties. This drug was introduced in 1999 for patients with moderate to severe active RA with early or late disease[12]. The drug act by inhibiting the dihydroorate dehydrogenase (DHODH) enzyme in the pyramidine synthesis resulting in the blockade of the proliferation T cell which needs high concentration of pyramidines. As the other cells derive pyramidines via alternate pathway they are not affected. Hence Leflunomide act as a cytostatic drug not as a cytotoxic drug. Monotherapy with leflunomide is as effective as methotrexate.To maintain a steady blood level an initial loading dose is required. The drug is gives as 100mg daily for 3 days followed by 20mg daily till the patient achieve remission. Then a maintenance dose of 10mg daily is continued. The major side effects are gastrointestinal (nausea, diarrheoa). Hepatotoxicity (elevation of transminases and jaundice), alopacia and reversible leucopenia. The drug is highly teratogenic and linkers in the body for more than two years Hence it is better avoided in females in the child bearing age. Prior to initiation of the drug, a complete blood counts and liver function tests must be performed and monitored every 4-8 weeks interval. In case of drug toxicity a drug wash out can be done using cholestyramine (6gms 3 times daily for 11 days). It is also suggested that men wishing to father a child should discontinue the drug and undergo an accelerated drug wash out procedure.

Other DMARDS
Drugs like Gold salts, D-pencillamine, Dapsone, Levamisole, Cyclosporin A, Gamma interferon, Azathroprine, Cyclophosphomide are not commonly used because of less efficacy and more toxicity and are used only when the other drugs are contraindicated or found to be less effective. For example parenteral gold is used in patients with liver diseases (where sulfasalazine methotrexate and Leflunomide are contraindicated), and cyclophosphomide is preferred in rheumatoid vasculitis.

Combination therapy with DMARDs
When a single DMARD alone is not fully efficacious to control the disease activity in RA, there is a recent trend to combine two or more DMARDs to improve the efficacy. In contrast to popular belief studies shows that combination of DMARDS rarely results in increased toxicity compared to the single DMARD control[13]. The common combination used are methotrexate with chloroquine or hydroxy chloroquine , methotrexate with sulfasalazine, methotrexate with leflunomide or triple therapy of methotrexate, sulfasalazine and hydroxy chloroquine.

Cytokine therapies
In RA there is a disequilibrium between proinflammatory and anti inflammatory cytokines. The tissue and serum levels of two important proinflammatory cytokines namely Tumor Necrosis Factor Alpha(TNFa) and Interleukin -1 (IL1) levels are high[19]. Recent advances in biotechnologically has led to the synthesis of compounds which can selectively inhibit these cytokines. The available biological agents today are either monoclonal antibodies or soluble receptors targeting these cytokines. 

Anti TNF drugs
Etanercept 
It is a soluble TNF receptor which is an engineered dimmer of P75 TNF receptor linked to FC portion of IgG. It is capable of binding to circulating or cell bound TNFa molecules and prevent it from binding to the cellular TNF receptor[14]. The half life of Etanercept is around 102 hours in adults. Hence is it given as 25mg subcutaneously twice weekly Etanercept has also been studied in combination with methotrexate and found to be useful in combination therapy. 

Infliximab
It is a chimeric monoclonal antibody. It effectively binds and neutralizes the action of circulating TNF a. The half life is longer than Etanercept ( 8-10 days). The recommended dosing is 3mg/kg initially at weeks 0,2,6 and thereafter every 8 weeks. The drug is given as intravenous infusion over 2 hours. Infliximab is also approved for use in RA in combination with methotrexate to reduce signs and symptoms and inhibit progression of structural damage, in patients with moderate to severe active disease who have had an inadequate response to methotrexate alone[15]. 

Adalimumab
It is a fully human Anti TNFa antibody which is less immunogenic than infliximab and has a longer half life[16]. The onset of action is also rapid and response will be evident in 1-7days after administration. Dose recommended is 40mg once in two weeks subcutaneously. 

Interleukin -1 Inhibitors 
Anakinra : It is recombinant interleukin - 1 receptor antagonist which inhibit the biological actions of the pro inflammatory cytokine IL-1[17]. It has a biological half life of 4-6hrs. The recommended dose is 100mg daily subcutaneously.

Side effects of anticytokine therapy

Increased chance of infection. Mycobacterial and bacterial infections are found to be high in patients receiving anti TNF drugs. It is a great concern in developing nations like India where these infections (especially tuberculosis) are otherwise prevalent in the community.
Autoimmune features.There are reports showing drug induced lupus in patients receiving anticytokine therapy even though the incidence is very rare.

Neurological dysfunction. Multiple sclerosis, optic neuritis and Guillian Barre syndrome has been reported following anti TNF therapy.
Haematological side effects. Pancytopenia and aplastic anemia are also reported in patients receiving prolonged anti TNF agents.

Corticosteroids

Corticosteroids are the most controversial drugs used in the treatment of RA, right from its introduction by Philip Hench in 1949 who won the Nobel Prize in 1950 for this discovery [18]. These drugs are highly potent anti-inflammatory agents with a wide range of actions. Steroids inhibit the recruitment of leukocytes at inflammatory sites by blocking the adhesion of these cells to endothelial cell wall. They also inhibit cellular activation and secretion of inflammatory mediators. Finally they block the tissue effects of many pro inflammatory cytokines. In spite of all these actions steroids lost their popularity due to the plethora of side effects, but are very useful drugs in chronic inflammatory arthritis like RA if judiciously used. The major indications of steroid the RA are given below.

1. Bridge therapy 
Because steroids are well known to suppress the synovitis rapidly and the recent data that they have disease modifying actions and has the ability to reduce radiological progression in the initial phase disease, steroids at lower doses can be used along with DMARDs in the first 2-3 months of the treatment. Once the DMARDs commences its action it should be taped off and stopped. The usual dose of steroid is 5 - 7.5 mg prednisolone daily or 80 - 120mg methyl prednisolone once in every 2-3 weeks. Long term use of even small dose steroids in RA should be strongly discouraged due to the side effects especially osteoporosis.

2. Extra articular disease
In cases of severe life threatening or sight threatening visceral involvement due to RA, high dose systemic steroids are strongly recommended. Examples are Rheumatoid vasculitis, scleritis, Intestitiallung disease, neuropathy or other extra articular disease. Prednisolone 40-60mg/day orally or intravenous methyl prednisolone 1gm/day for 3 days followed by oral prednisolone is recommended in these cases which can be tapered of slowly 

3. Pregnancy
In pregnancy almost all NSAIDS and many of the DMARDS (except sulfasalazine and hydroxy chloroquine which are relatively safe) are contra indicated, low dose prednisolone at a dose of 5-15mg/day can be tried as prednisolone will not cross the placenta at this dose.

4. Intraarticular / intralesional steroids
Local steroid injections are useful in relieving synovitis if one or two joints are out of proportionately inflammed compared to generalised disease activity. Intra lesional steroids are also useful in teno synovitis, bursitis and carpal tunnel syndrome. 

5. Refractory RA
When arthritis is refractory to all other mode of therapy (NSAIDs, Combination of DMARDS and biological agents). Low dose oral steroids may be the only choice. But as far as possible oral steroids should be taped off once the disease activity has come down. 

Newer/ Investigational therapies 

Prosorba column
Plasmapheresis to remove IgG and IgG containing immune complexes from plasma is an established therapeutic procedure in RA. US FDA has approved an extra corporal immuno absorption column called prosorba column for aphaeresis in patients with long standing moderate to severe RA[20]. It is a proven and effective alternative therapeutic option in patients with severe RA refractory to several DMARDs.

Pegsunercept : 
Polyethylene glycated soluble TNF receptors produced by recombinant DNA technology is under phase II clinical trial. It has longer half life than etanercept.

Prainacasan
It is an oral interleukin-1 converting enzyme inhibitor (ICEI). It is under phase II clinical trial at a dose of 300 - 1200mg/day for active RA.
Vaccine therapy
T cell receptor peptide vaccine has been evaluated for prevention of RA which shows marginal trend towards improvement in signs and symptoms compared to placebo. Better vaccines are under trial.

Other newer drugs

Rituximab (B cell depleting drug) CTLA4 Ig (Antibody preventing interaction with CD28 receptors and causing T cell inhibition). Anti interleukin-6 antibody , gene therapy and stem cell transplant are all under extensive trial. Even though the initial experience of these therapies are encouraging, the long term outcomes in terms of efficacy and safety, only will eventually establish their place in the pharmacotherapy of RA.

References 

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