Question

Explain the fact that biologic DMARDs require a trial period of 3-6 months to judge their efficacies.

Also explain the fact that RA increases the risk of osteoporosis, CV diseases and chronic kidney disease.

Answer 1

Disease-modifying antirheumatic drugs (DMARDs) are a class of drugs indicated for the treatment of inflammatory arthritides including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). They can also be used to in the treatment of other disorders including connective tissue disease such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and Sjogren syndrome (SS), as well as in treatment of inflammatory myositis, vasculitis, uveitis, inflammatory bowel disease, and some types of cancers.

DMARDs are immunosuppressive and immunomodulatory agents and are classified as either conventional DMARDs or biologic DMARDs. Commonly used conventional DMARDs include methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. Biologic DMARDs were introduced in the early 1990s and are usually prescribed after the failure of conventional DMARD therapy Some biologic agents include infliximab, adalimumab, etanercept, rituximab, abatacept, rituximab, tocilizumab, tofacitinib, among others. Biologic DMARDs are highly specific and target a specific pathway of the immune system. Some of these drugs are monoclonal chimeric humanized fusions antibodies, while others are receptors that have been fused to a part of the human immunoglobulin or small molecules such as Janus kinase (JAK) inhibitors.

#DMARDs in rheumatoid arthritis-

Although many medications can be used in the treatment of RA, methotrexate is the most commonly used agent as an initial treatment. RA treatment is complicated with several factors playing a role in decision making, including disease activity and severity, comorbidities, and patient preference . RA treatment can be either monotherapy or combination therapy, although several randomized controlled trials have shown the superiority of combination therapy of a biologic DMARD with a conventional DMARD such as methotrexate over either agent alone. Treatment goals shall include achieving remission or low disease activity, as well as prevent radiographic progression of the disease. The initiation of therapy early in the disease has shown to prevent radiographic progression, most of which occurs within the first few months of the disease.

# Mechanism of Action-

Each DMARD has a unique mechanism of action ultimately interfering with critical pathways in the inflammatory cascade. Methotrexate, for example, stimulates adenosine release from fibroblasts, reduces neutrophil adhesion, inhibits leukotriene B4 synthesis by neutrophils, inhibits local IL-1 production, reduces levels of IL-6 and IL-8, suppresses cell-mediated immunity, and inhibits synovial collagenase gene expression. Other medications in this class serve to inhibit proliferation or cause dysfunction of lymphocytes. Leflunomide inhibits dihydroorotate dehydrogenase resulting in inhibition of pyrimidine synthesis hence blocking lymphocyte proliferation. Sulfasalazine mediates its anti-inflammatory effects by preventing oxidative, nitrative and nitrosative damage. Hydroxychloroquine, on the other hand, is a very mild immunomodulatory agent that inhibits intracellular toll-like receptor TLR9.

Biologics, on the other hand, are very selective in their mechanism of action. The overarching functions of biologics include interfering with cytokine function or production, inhibiting the “second signal” required for T-cell activation, depleting B-cells or inhibiting factors that active B-cells. Tofacitinib is a small molecule inhibitor of JAK, a protein tyrosine kinase involved in mediating cytokine signaling.

# Osteoporosis -related to various factors including menopause and aging- is the most common chronic metabolic bone disease, which is characterized by increased bone fragility. Although it is seen in all age groups, gender, and races, it is more common in Caucasians, older people, and women. With an aging population and longer life span, osteoporosis is increasingly becoming a global epidemic. Currently, it has been estimated that more than people are suffering from osteoporosis. recent statistics from the International Osteoporosis Foundation, worldwide, 1 in 3 women over the age of 50 years and 1 in 5 men will experience osteoporotic fractures in their lifetime. Every fracture is a sign of another impending one. Osteoporosis has no clinical manifestations until there is a fracture. Fractures cause important morbidity; in men, in particular, they can cause mortality. Moreover, osteoporosis results in a decreased quality of life, increased disability-adjusted life span, and big financial burden to health insurance systems of countries that are responsible for the care of such patients. With an early diagnosis of this disease before fractures occur and by assessing the bone mineral density and with early treatment, osteoporosis can be prevented. Therefore, increasing awareness among doctors, which, in turn, facilitates increase awareness of the normal populace, will be effective in preventing this epidemic