Anti-rheumatoid Drugs

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Chapter: Essential pharmacology : Antirheumatoid and Antigout Drugs

These are drugs which (except corticosteroids), can suppress the rheumatoid process and bring about a remission, but do not have nonspecific anti-inflammatory or analgesic action.



These are drugs which (except corticosteroids), can suppress the rheumatoid process and bring about a remission, but do not have nonspecific anti-inflammatory or analgesic action. They are used in rheumatoid arthritis (RA) in addition to NSAIDs and are also referred to as disease modifying antirheumatic drugs (DMARDs) or slow acting antirheumatic drugs (SAARDs). The onset of benefit with DMARDs takes a few months of regular treatment and relapses occur a few months after cessation of therapy. Recently, some biologic response modifiers (BRMs) have been added for resistant cases.


Rheumatoid arthritis (RA) is an autoimmune disease in which there is joint inflammation, synovial proliferation and destruction of articular cartilage. Immune complexes composed of IgM activate complement and release cytokines (mainly TNFα and IL1) which are chemotactic for neutrophils. These inflammatory cells secrete lysosomal enzymes which damage cartilage and erode bone, while PGs produced in the process cause vasodilatation and pain. RA is a chronic progressive, crippling disorder with a waxing and waning course. NSAIDs are the first line drugs and afford symptomatic relief in pain, swelling, morning stiffness, immobility, but do not arrest the disease process.


The goals of drug therapy in RA are:


·        Ameliorate pain, swelling and joint stiffness

·        Prevent articular cartilage damage and bony erosions

·        Prevent deformity and preserve joint function.


Though mild/early cases are still mostly treated only with NSAIDs, the current recommendation is to add DMARDs as soon as the diagnosis of RA is confirmed. However, use of DMARDs in early/mild RA should be weighed against their potential adverse effects, which may be serious. More than one DMARD may be used concurrently; advanced cases may require 2 or 3 drugs together, because all DMARDs tend to lose effectiveness with time.


A. Disease modifying antirheumatic drugs (DMARDs)


1.     Immunosuppressants: Methotrexate, Azathioprine, Cyclosporine

2.     Sulfasalazine

3.     Chloroquine or Hydroxychloroquine

4.     Leflunomide

5.     Gold sod. thiomalate, Auranofin

6.     d-Penicillamine


B. Biologic response modifiers (BRMs)


1.   TNFα inhibitors: Etanercept, Infliximab, Adalimumab

2.   IL1 antagonist: Anakinra


C. Adjuvant drugs


Corticosteroids: Prednisolone and others


1. Immunosuppressants


Methotrexate (Mtx) This dihydrofolate reductase inhibitor has prominent immunosuppressant and anti-inflammatory property. Beneficial effects in RA are probably related to inhibition of cytokine production, chemotaxis and cellmediated immune reaction. Induction of oral lowdose (7.5–15 mg) weekly Mtx regimen has improved acceptability of this drug in RA. Onset of symptom relief is relatively rapid (4–6 weeks), therefore preferred for initial treatment. Mtx is now the DMARD of first choice and the standard treatment for most patients, including cases of juvenile RA. Response is more predictable and sustained over longterm.


Oral bioavailability of Mtx is variable and may be affected by food. Its excretion is hindered in renal disease: not recommended for such patients. Probenecid and aspirin increase Mtx levels and toxicity. Trimethoprim can add to inhibition of dihydrofolate reductase and depress bone marrow. Nodulosis, oral ulceration and g.i. upset are the major side effects of low dose Mtx regimen. With prolonged therapy, dose dependent progressive liver damage leading to cirrhosis occurs in some patients (this is not seen with short courses used in cancer). Incidence of chest infection is increased. Mtx is contraindicated in pregnancy, breastfeeding, liver disease, active infection, leucopenia and peptic ulcer.




Azathioprine This purine antimetabolite acts after getting converted to 6mercaptopurine by the enzyme thiopurine methyl transferase (TPMT). It is a potent suppressant of cell-mediated immunity; appears to selectively affect differentiation and function of Tcells and natural killer cells. It also suppresses inflammation. However, remission is induced in smaller percentage of RA patients and it is less commonly used. Given along with corticosteroids, it has a steroid sparing effect, for which it is primarily used now, especially in cases with systemic manifestations. It is not combined with Mtx.


Dose: 50–150 mg/day; IMURAN 50 mg tab.


Other immunosuppressants like cyclosporine, chlorambucil, cyclophosphamide are rarely used in RA; are reserved for cases not responding to other DMARDs.


3.     Sulfasalazine


It is a compound of sulfapyridine and 5amino salicylic acid (5ASA); has anti-inflammatory activity and is primarily used in ulcerative colitis. In addition, it suppresses the disease in significant number of RA patients. The mechanism of action is not known. Sulfapyridine split off in the colon by bacterial action and absorbed systemically appears to be the active moiety (contrast ulcerative colitis, in which 5ASA acting locally in the colon is the active component). Generation of superoxide radicals and cytokine elaboration by inflammatory cells may be suppressed. Efficacy of sulfasalazine in RA is modest and side effects are few, but neutropenia/thrombocytopenia occurs in about 10% patients and hepatitis is possible. It is used as a second line drug for milder cases.


Dose: 1–3 g/day in 2–3 divided doses.




4. Chloroquine And Hydroxychloroquine


These are antimalarial drugs found to induce remission in upto 50% patients of RA, but take 3–6 months. Their advantage is relatively low toxicity, but efficacy is also low; bony erosions are not prevented. Their mechanism of action is not known, however, they have been found to reduce monocyte IL–I, consequently inhibiting B lymphocytes. Antigen processing may be interfered with. Lysosomal stabilization and free radical scavenging are the other proposed mechanisms.


For RA, these drugs have to be given for long periods: accumulate in tissues and produce toxicity, most disturbing of which is retinal damage and corneal opacity. This is less common and reversible in case of hydroxychloroquine, which is preferred over chloroquine.


Other adverse effects are rashes, graying of hair, irritable bowel syndrome, myopathy and neuropathy.


Chloroquine/hydroxychloroquine are employed in milder nonerosive disease, especially when only one or a few joints are involved, or they are combined with Mtx/sulfasalazine.


Dose: Chloroquine 150 mg (base) per day. Hydroxychloroquine 400 mg/day for 4–6 weeks, followed by 200 mg/day for maintenance.


5. Leflunomide


This immunomodulator inhibits proliferation of activated lymphocytes in patients with active RA. Arthritic symptoms are suppressed and radiological progression of disease is retarded. In clinical trials its efficacy has been rated comparable to Mtx and onset of benefit is as fast (4 weeks).


Leflunomide is rapidly converted in the body to an active metabolite which inhibits dihydroorotate dehydrogenase and pyrimidine synthesis in actively dividing cells. Antibody production by Bcells may be depressed. The active metabolite has a long t½ of 2 weeks; leflunomide, therefore, is given in a loading dose of 100 mg daily for 3 days followed by 20 mg OD.


Adverse effects of leflunomide are diarrhoea, headache, nausea, rashes, loss of hair, thrombocytopenia, leucopenia, increased chances of chest infection and raised hepatic transaminases. It is not to be used in children and pregnant/ lactating women. Leflunomide is an alternative to Mtx or can be added to it, but the combination is more hepatotoxic. Combination with sulfasalazine improves benefit.


LEFRA 10 mg, 20 mg tabs.


Gold Gold is considered to be the most effective agent for arresting the rheumatoid process and preventing involvement of additional joints. It was the standard DMARD before the advent of low dose Mtx regimen. A remission is induced in over half of the patients. It reduces chemotaxis, phagocytosis, macrophage and lysosomal activity, monocyte differentiation and inhibits cell mediated immunity (CMI). Rheumatoid factor levels and ESR are lowered. By an effect on synovial membrane and collagen, it prevents joint destruction; may induce healing of bony erosions. It is effective in psoriatic arthropathy also.


Gold is heavily bound to plasma and tissue proteins, especially in kidney : stays in the body for years.


Toxicity of parenteral gold salt (hypotension, dermatitis, stomatitis, kidney and liver damage, bone marrow depression) is high. It is rarely used now.


Auranofin It is an orally active gold compound containing 29% gold, with a bioavailability of 25%. Plasma gold levels and efficacy are lower than with injected gold sod. thiomalate, but it is less toxic. Main adverse effect is diarrhoea (30% incidence) and abdominal cramps. Others are: pruritus, taste disturbances, mild anaemia and alopecia. Auranofin is used infrequently.


Dose: 6 mg/day in 1 or 2 doses; RIDAURA 3 mg cap, GOLDAR 3 mg tab.


6. d-Penicillamine


It is a copper chelating agent (see Ch. No. 66) with a gold-like action in RA, but less efficacious; bony erosions do not heal. It is not favoured now because it does not offer any advantage in terms of toxicity, which is similar to that of gold. Loss of taste, systemic lupus and myasthenia gravis are the other adverse effects.


Penicillamine increases soluble collagen and is the preferred drug for stage II and III scleroderma.


Dose: start with 125–250 mg OD, then 250 mg BD; ARTIN 150, 200 mg caps; CILAMIN 250 mg cap.


7.    Biologic response modifiers


Recently, several recombinant proteins/monoclonal antibodies that bind and inhibit cytokines, especially TNFα or IL1 have been produced and found to afford substantial benefit in autoimmune diseases like RA, inflammatory bowel diseases, psoriasis, scleroderma, etc.


TNFα Inhibitors


Because TNFα plays a key role in the inflammatory cascade of RA by activating membrane bound receptors (TNFR1 and TNFR2) on the surface of T-cells, macrophages, etc., exogenously administered soluble TNF-receptor protein or antibody can neutralize it and interrupt the reaction. TNF inhibitors mainly suppress macrophage and T-cell function; inflammatory changes in the joint regress and new erosions are slowed. Quicker response than DMARDs has been obtained. Though effective as monotherapy, they are generally added to Mtx when response to the latter is not adequate or in rapidly progressing cases. Side effects are few, but susceptibility to opportunistic infections, including tuberculosis and pneumocystis pneumonia is increased. All are very expensive.


Etanercept: It is a recombinant fusion protein of TNF-receptor and Fc portion of human IgG1; administered by s.c. injection 50 mg weekly. Pain, redness, itching and swelling occur at injection site and chest infections may be increased, but immunogenicity is not a clinical problem.


Infliximab: It is a chimeral monoclonal antibody which binds and neutralizes TNFα; 3–5 mg/kg is infused i.v. every 4–8 weeks. An acute reaction comprising of fever, chills, urticaria, bronchospasm, rarely anaphylaxis may follow the infusion. Susceptibility to respiratory infections is increased and worsening of CHF has been noted. It is usually combined with Mtx which improves the response and decreases antibody formation against infliximab.


Adalimumab: This recombinant monoclonal antiTNF antibody is administered s.c. 40 mg every 2 weeks. Injection site reaction and respiratory infections are the common adverse effects. Combination with Mtx is advised to improve the response and decrease antibody formation.


IL1 Antagonist


Anakinra: It is a recombinant human IL1 receptor antagonist. Though clinically less effective than TNF inhibitors, it has been used in cases who have failed on one or more DMARDs.


Dose: 100 mg s.c. daily.


Local reaction and chest infections are the main adverse effects.


8.     Corticosteroids


They have potent immunosuppressant and anti-inflammatory activity: can be inducted almost at any stage in RA along with first or second line drugs, if potent anti-inflammatory action is required while continuing the NSAID ± DMARD. Symptomatic releif is prompt, but they do not arrest the rheumatoid process, though joint destruction may be slowed and bony erosions delayed.


Long term use of corticosteroids carries serious disadvantages. Therefore, either low doses (5–10 mg prednisolone or equivalent) are used to supplement NSAIDs (once used in this manner, it is difficult to withdraw steroids—exacerbation is precipitated: patient becomes steroid dependent), or high doses are employed over short periods in cases with severe systemic manifestations (organ threatening disease, vasculitis) while the patient awaits response from a remission inducing drug.


In cases with single or few joint involvement with severe symptoms, intraarticular injection of a soluble glucocorticoid affords relief for several weeks; joint damage may be slowed. However, this procedure should not be repeated before 4–6 months.


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