Chronic Autoimmune Diseases

Multiple sclerosis (MS), Systemic lupus erythematosus (SLE) and Rheumatoid arthritis (RA) are all chronic autoimmune conditions characterised by relapse and remission, premature mortality, work disability and reduced quality of life for patients. For all three conditions, treatments are available that aim to control the systemic inflammation and autoimmune process, but each treatment will only induce remission in a subset of patients and results in high treatment costs.

Multiple sclerosis
It is estimated that 700,000 people in Europe have MS and it is second only to road traffic accidents as a cause of disability in young people. Whilst the condition varies in its clinical course and severity, 50% patients leave the workforce within 3 years of diagnosis and 10-15% require a wheelchair eventually. Costs have increased in recent years due to the availability of newer, more expensive therapies and increasing prevalence of the condition.
In the case of MS, besides immunomodulatory drugs, used in the last two decades for the treatment of RRMS, many biological compounds have been developed including inhibitors of specific immune cell subsets or blockers of lymphocyte migration into the brain. In addition, new immunomodulatory drugs have been produced, to avoid the flu-like effect that may occur in some patients and to prolong the half-life of drugs, thus avoiding daily infusions. The response to immunomodulatory drugs is unpredictable and rate of responders is about 30%. New biological drugs are more effective, but associated with more risks (such as progressive multifocal leukoencephalopathy with Natalizumab). As the course of the disease cannot be predicted at diagnosis, there are difficulties in choosing the treatment.
Systemic lupus erythematosus
SLE is a chronic, multisystem autoimmune disorder associated with significant premature mortality, being a leading cause of cardiovascular mortality in young women. Fewer treatment options are available and the disease imposes a significant burden on health-related quality of life, equivalent to diabetes and congestive heart failure.
As for treatment options, SLE is in a rather disadvantageous position with only one drug approved in the last 50 years (Belimumab). Research on new therapies for this condition is hampered by the fact that it is a multi-organ disease characterised by alternating periods of disease activity and remission. Patients may receive several drug combinations as standard of care, including corticosteroids, non-steroidal anti-inflammatory drugs, anti-malarials and immunosuppressive/cytotoxic drugs. In recent years, the treatment of several lupus manifestations, especially nephritis, has improved with the use of new immunosuppressive agents such as mycophelonate mofetil (MMF). Additionally, a few biological agents, mainly rituximab, have been widely used in Europe as an off-label treatment in patients with refractory disease. However, with the exception of belimumab, an anti-B lymphocyte stimulator (BLyS) tageted therapy, all the other biological agents that have been tested (i.e., rituximab, ocrelizumab, epratuzumab) have failed to demonstrate efficacy in randomised controlled trials, mainly due to difficulties in trial design.
Rheumatoid arthritis
RA is characterised by synovial joint inflammation and – despite major advances in treatment – is still associated with premature mortality of up to 3-fold compared with the general population. It is the commonest of these autoimmune diseases, affecting ~1% adults. However, in face of a rapidly aging population, the number of patients affected will increase significantly in the next 20 years. The treatment landscape for patients with RA has changed dramatically over the last 20 years with the advent of biological and targeted therapies developed and designed to block the underlying inflammatory pathways that are unregulated in the disease. There has also been better and earlier use of existing disease modifying anti-rheumatic drugs (DMARDs) and these remain the first option for patients with new-onset inflammatory arthritis.
Methotrexate is the most commonly prescribed first-choice DMARD, but by 2 years, only 55% remain on this inexpensive therapy. Patients who fail to respond to MTX and at least one other DMARD are eligible for biologic drugs including TNF inhibitors, interleukin 6 inhibitors, co-stimulatory blockers or targeted oral therapies that act on the JAK/STAT pathway. While drug costs are high, only ~20% patients will do well, whilst ~20% will not respond at all. The biologic drugs tend to be prescribed according to the order in which they came to market rather than by informed, rational decisions yet introduction of early, effective therapy has consistently been shown to improve long-term outcomes including joint damage, disability and employment. However, we currently have no biomarkers to match the right treatments to the right patient.