Saturday, April 01, 2006

Steroids 2

Steroids and the immune response.

If you get put off by technical language you should skip the next three paragraphs.

Corticosteroids acts through intracellular receptors, which are present in almost every cell in the body. The receptors are present in the cytoplasm of the cell often bound to the chaperoning protein HSP-90 (remember that from ZAP-70?). On binding the steroid the receptor is freed from the HSP-90 and this exposes its DNA-binding region. The steroid-receptor complex then crosses the nuclear membrane into the nucleus and binds to DNA. It has been estimated that the expression of as many as 1% of all genes is regulated by the steroid receptor, which accounts for the multiple effects of the hormone.

In general pharmacological doses of steroids are anti-inflammatory. They suppress the production of a number of inflammatory cytokines such as IL-1, TNF-a, GM-CSF, IL-3, IL-4, IL-5, IL-8, as well as prostaglandins, leukotrienes and adhesion molecules, but the production of other proteins such as endonucleases and lipocortin-1 is increased.

Of all the cells in the immune system, macrophages are the most affected. Normally they
home to sites of inflammation and take part in antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). Corticosteroids down-regulate the expression of Fc and C3b receptors on macrophages and reduce the secretion of pro-inflammatory cytokines and eicosanoids. Expression of class II histocompatibility molecules is reduced, which in turn inhibits antigen presentation. Expression of adhesion molecules is inhibited, which reduces cell-cell interactions.

So what does all this mean? Steroids are used first and foremost to quieten down inflammation. In diseases like rheumatoid arthritis the pain and swelling heat and redness of the joint are all calmed down by the use of steroids, but there are lots of other diseases where a similar process is going on with macrophages acting in concert with antibody. Patients with CLL will know all about autoimmune hemolytic anemia and immune thrombocytopenia. In both of these an antibody kills the affected cell with the help of a macrophage. Steroids work in these conditions, not by getting rid of the antibody, but by paralyzing the macrophages. But there is a corollary for CLL patients. Antibodies like rituximab rely on macrophages to help them kill the CLL cells. If steroids are given with the antibody, they are likely to lessen their effect.

Another major effect of steroids is to quieten down allergic reactions. This is where those difficult words leukotrienes and eicosanoids come in. The eicosanoids are a family of locally active hormones derived from the twenty carbon fatty acid arachidonic acid. Most members of this family have roles in inflammation, including regulation of vasodilatation, vascular permeability, pain and the recruitment of white cells. The eicosanoid family includes prostaglandins, thromboxanes, leukotrienes and prostacyclins. Leukotrienes cause smooth muscle to contract, increase the permeability of blood vessels and stimulate the secretion of mucus. You can see how this would be involved in asthma, and, of course, steroids are the most useful drugs in treating asthma.

The thromboxanes and prostacyclins as well as being involved in inflammation are important in clotting via the platelets and the blood vessel walls. The synthesis of the prostaglandins involves enzymes known as cycloxygenases often abbreviated to Cox. The recent anxiety over Vioxx related to its role as an inhibitor of Cox. There are very many inhibitors of cycloxygenases – they include drugs like ibuprofen and diclofenac. These drugs have unwanted side effects, particularly bleeding from the stomach. Because of this pharmaceutical firms have tried to inhibit different forms of the enzymes separately. Inhibiting Cox-2 rather than Cox-1 should avoid the bleeding problems. Unfortunately it looks as though this increases the risk of thrombosis.

As well as their effects in quelling inflammation, steroids also have effects on lymphocytes. In T cells, particularly early in their life span, steroids induce apoptosis, although this can be stopped by certain hormones like prolactin, or by signaling trough the T cell receptor or by 17-AAG. B lymphocytes also can be sent into apoptosis by steroids, though again they are more resistant later in their development.

All in all treatment with steroids suppresses inflammation in many and varied ways and also has a rather unpredictable effect on specific immunity. This means that patients on steroids may have their primary disease quelled, but at the same time they become susceptible to infections. The most likely infections are fungal, some bacteria such as TB and viral. More than this, the normal response to infection – fever and feeling unwell – may be absent so a patient may get very sick without the tell-tale signs being noticed.

So the side effects of steroids begin to add up. Diabetes, high blood pressure, thinning of the bones, shape changes of the face and body, fluid retention, acne, striae, muscle wasting, psychological changes and now infections; powerful drugs they may be, but most doctors are reluctant to use them except in short courses.


Anonymous said...

You comment that the administration of steriods, including I would think methylprednisolone, impair the ability of rituximab to kill CLL cells.

Yet, one of the treatments in clinical trials now involve just that pairing; dosing with methylprednisolone just prior to the administration of rituximab.

In fact, the newer trial of HDMP+rituximab involves shortening the time between the corticosteroid dosing and giving the rituximab.

There used to be three days between doses, now there is one day (as I understand it).

Is this going in the wrong direction?

Terry Hamblin said...

This is an interesting thought. High doses of methylprednisolone are very lympholytic and kill by inducing apoptosis. Although rituximab mainly kills by evoking effector mechanisms, which are at least partially paralyzed by steroids, it can also itself induce apoptosis directly. There has been some suggestion that agents that induce apoptosis can have a synergistic effect when used together, in other words the sum of their combined effects is greater than the individual parts.

Inour antibody trials we have always asked investigators to avoind giving steroids. The "allergic" reactions to the infusions would be a,eliorated by steroids,. but would they also ameliorate the therapeutic effect?

David Arenson said...

As you know, the R + HDMP trial at UCSD has caught the attention of patients who are looking for a way to avoid the myelosuppression and toxicities of chemotherapy, and it is seen as a possible stopgap that avoids "using up" alkalytors and purine analogues, which decline in effectiveness as drug resistance develops.

So, a few more questions, if I might:

1. Does drug resistance develop to HDMP or other steroids -- or could one repeat HDMP every few years and expect similar results each time?

2. The last paragraph of your post indicates some of the downsides of steroids if used long-term. What is your view of the use of HDMP, as at UCSD, restricted to a period of a few months? There has been some debate about whether the quantity used is relatively safe or not, and an argument that has been made in its favor is that high doses at short duration should not lead to the same problems as long-term, lower-dose usage. Your thoughts?

3. On the whole, which is more immunosuppressive, a course of HDMP or a course of fludarabine? (Or, to put it another way, which one is potentially worse for you?)

4. Finally, some of the participants in the UCSD trial have received MRD-negative responses following administration of a course of Sub-Q Campath six months or so after the end of the R + HDMP. On the grand scale of risk-reward, doesn't this approach seem somewhat better, if avoiding toxicity and refractory disease are goals, than achieving the same result via RFC, CFAR or the like?

Terry Hamblin said...

These are questions I will address in Steroids 3. My aim in this article was to address the mechanism of action of corticosteroids. Before I did the research I only knew from a practical point of view what they did.

Sylvie said...

Terry, what do you think of the use of methylprednisolone on its own as a gentler path than chemo?