RHEUMATOID ARTHRITIS MANAGEMENT

Binding to dihydrofolate reductase

Ans. is ‘b’ i.e., Vincristine

Disease modifying antirheumatic drugs (DMARDs) :‑

1. Immunosuppresants Methotrexate, azathioprine, cyclosporine
2. Sulfasalazine
3. Choloroquine or hydroxychloroquine
4. Leflunomide
5. Gold sod. thiomalate, Auranofin
6. d – Penicillamine

Ans. is `a’ i.e., CD20

Answer is B (Rheumatoid arthritis) :

Chrysotherapy (Gold salts): are used as a disease-modifying anti-rheumatic drug for patients who fail to improve on or who cannot tolerate methotrexate.

Intramuscular gold is used most often as it is more effective than oral gold.

Ans. is ‘c’ i.e., IL 6

Tocilizumab

• It is the antibody directed against IL 6 receptor

It is approved for use in :

1. Rheumatoid arthritis
2. Neuromyelitisoptica
3. Castleman’s disease
4. Systemic juvenile idiopathic arthritis

Ans. c. Rheumatoid arthritis

Abatacept, a new drug inhibiting co-stimulation is used for the treatment of Rheumatoid arthritis.

Abatacept is a soluble fusion protein consisting of the extracellular domain of human cytotoxic T lymphocyte– associated antigen 4 (CTLA-4) linked to the modified portion of human IgG. It inhibits the co-stimulation of T cells by blocking CD28-CD80/86 interactions and may also inhibit the function of antigen-presenting cells by reverse signaling through CD80 and CD86. Abatacept has been shown in clinical trials to reduce disease activity, slow radiographic progression of damage, and improve functional disability. Most patients receive abatacept in combination with methotrexate or another DMARD such as leflunomide. Its onset of action is usually slower than that of the anti- TNF agents. Abatacept therapy has been associated with an increased risk of infection but is usually well tolerated otherwise.’

Abatacept

• Abatacept is a soluble fusion protein consisting of the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) linked to the modified portion of human IgGQ.

Mechanism of Action:

• Inhibits the co-stimulation of T cells by blocking CD28-CD80/86 interactions0
• Also inhibit the function of antigen-presenting cells by reverse signaling⁰ through CD80 and CD86.
• Onset of action is usually slower than that of the anti-TNF agents.

Indications:

• Abatacept has been shown in clinical trials to reduce disease activity, slow radiographic progression of damage, and improve functional disability in rheumatoid arthritisQ.
• Most patients receive abatacept in combination with methotrexate or another DMARD such as leflunomide.

Adverse-effects:

• Associated with an increased risk of infectionQ

Ans. is ‘c’ i.e., Corticosteroids 

Ans. is ‘b’ i.e., Inhibitor of co-stimulation of T cells

Biologic response modifier (BRMs)

• Several recombinant proteins/monoclonal antibodies that bind and inhibit cytokines, especially TNFa or IL-1 have been used succesfully in autoimmune diseases like RA, IBD, psoriosis or scleroderma.

A) TNF-a inhibitors

• TNF-a plays a key role in the inflammatory cascade of RA by activating membrane bound receptors (TNFR, and TNFR₂) on the surface of T-cell and macrophages.
• TNF inhibitors mainly suppress macrophages and T cell function –> inflammatory changes in the joint regress and new erosion is slowed.
• Response is quicker than DMRADs.
• Though effective as monotherapy, they are generally added to methotrexate when response to the latter is not adqeuate 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 IgG
• It is administered by S.C. injection.
• Infliximab
• It is a chimeral monoclonol antibody which binds and neutralizes TNF-a.
• It is given by i.v. route.
• It is indicated in RA, psoriotic arthritis, Crohn’s disease, Wegener’s granulomatosis and sarcoidosis.
• Adalimumab
• This recombinant monoclonal anti-TNF antibody.
• It is administered by S.C. route.

B) IL-1 antagonist

Anakinra

• It is a recombinant human IL-I receptor antagonist. 
• It is less effective than TNF inhibitors.
• It is administered by S.C. route.

C.T-cell costimulatory blockers

Abatacept

• It is a fusion protein that combines the extracellular domain of the molecule CTLA4 (CD 154) with the Fc portion of a human immunoglobulin.
• It interfere with the interactions between antigen presenting cells and T lymphocytes. Therefore, it affects early stages in the pathogenic cascade of event in RA.
• CTLA4 has high affinity for CD 28, when abatacept binds to CD28 on T cell surface, it prevents the second signal from being delivered, thus turning down the T cell response.
• Additional effects are decreasing the production of T cell derived cytokines including TNF.

D.  B-cell depleters

Rituximab

• B-cells are inflammatory cells with multiple functions in the immune response. The depletion of B cells has been shown to be effective in reducing signs and symptoms of RA and in slowing radiographic progression. o Rituximab is a chimeric monoclonal antibody that binds to the CD20 molecule on the B cell surface leading to the removal of B cells from the circulation.

Ans. is ‘a’ i.e., Anakinra