On the other hand, I’m not sure about tolerance either.
It’s not obvious, but “tolerance” comes from the Latin word ferre, to carry, whose principal parts, from different roots, are ferro, ferre, tuli, latum (see BMJ 2000;320:625). And “tolerance” carries several technical meanings.
Pharmacological tolerance can be acquired or natural. Acquired tolerance is reduced sensitivity to a drug, from previous exposure either to it or (cross-tolerance) to another drug. It should not be confused with tachyphylaxis or …
The relationship of a comorbidity to a rheumatic disease and its treatment cannot be answered in standard efficacy trials. Registries, very large safety trials addressing a specific comorbidity and evaluation of large clinical databases are more likely to help answer these questions.
A patient with severe AS has failed three NSAIDs. He has significantly reduced activities of daily living with a BASDAI of 7. He had a blood transfusion several years ago after an automobile accident and has been found to have active hepatitis B and C. Would you treat him with a TNF inhibitor?
In addition, comorbidities can affect outcome measures often used when assessing efficacy of an intervention. For example, RA patients with a high comorbidity burden often report elevated global health scores, which may increase their disease activity scores, even in the absence of elevated inflammatory markers or swollen and tender joint counts [ 2]. Therefore, a treatment that has shown high rates of disease remission in a clinical trial (where certain comorbidities may have been excluded) may seem to be much less efficacious when assessed in an unselected clinical population. While this scenario reflects the limitations to accurately assess disease activity and remission in rheumatic disease conditions, it also highlights the importance of accurately assessing comorbidity when measuring disease outcomes that are reliant on self-report of global health.
These trials are also generally carried out in a population with an underlying disease, but who are otherwise healthy. In many trials involving patients with a disease that affects the immune system, such as RA, PsA, AS and SLE, patients are excluded if they have significant comorbidities such as cardiac, endocrine, renal, pulmonary or neurological disease. They will certainly be excluded if they are pregnant, breastfeeding, have an underlying infection, have a history of opportunistic infection (or risk of an opportunistic infection) or have a malignancy or a history of malignancy. In other rheumatic diseases, such as gout and OA, it is usual to exclude patients with compromised renal or cardiac function, although many of the patients we see clinically have these problems. Many medications are metabolized in the liver; despite which, patients with compromised hepatic function are excluded from many clinical trials as well.
With this in mind, how are we to determine in which patient is a medication safe and well tolerated? A patient presents with classic signs and symptoms of seropositive, erosive RA. Many studies suggest that the patient should initially be treated with MTX, but if the patient is a 25-year-old recently married female who hopes to become pregnant in the near future, drinks two glasses of wine a day and works as a phlebotomist in a drug addiction centre, is this really the correct choice of initial therapy? What is her risk : benefit ratio with MTX? And, if MTX should not be used, what medication should be started? If she fails to respond to initial therapy, should a biologic drug be used?
The issue of comorbidities and how they affect disease state and the use of medications is not just an issue in the treatment of RA; the understanding of the effects of comorbidities on disease management is important in the treatment of all rheumatic diseases.
Not all comorbidities preclude the use of specific medications. The more we learn about the significance of a comorbidity in a specific disease and how to treat the comorbidity itself or how to treat around the comorbidity, the more effective we become as physicians. An example is tuberculosis and the use of TNF inhibitors. When TNF inhibitors were first introduced into clinical practice as a treatment for RA, it was not known that patients with latent tuberculosis were at risk of developing disseminated tuberculosis. After 70 cases of tuberculosis were described within a year of the approval of use of TNF inhibitors, primarily with the use of an mAb to TNF, it became apparent that patients required stringent screening for latent tuberculosis, a significant comorbidity [ 1]. If latent tuberculosis was found, then appropriate treatment, generally isoniazid, if started simultaneously with the TNF inhibitor, virtually always prevented the development of active, disseminated tuberculosis.