Index:

Mechanism of action
General use - advice
Weaning in RA
Steroids in psoriasis
Steroids in Systemic disease

Mechanism of Activity

Free cortisol diffuses into individual cells where specific receptor proteins are found in the cytoplasm of corticosteroid-responsive tissues .
The receptor gene has now been cloned and sequenced.
The corticosteroid receptor belongs to a super family of regulatory proteins that include receptors for thyroid hormones and the vitamin A-related metabolite, retinoic acid .
The corticosteroid and receptor form a complex that undergoes a conformational change, leaves the cytoplasm and moves to the nucleus, where it binds reversibly to specific sites on chromatin.
This results in the production of mRNA, which codes for enzymes or other proteins that produce the hormonal effects.
Responses can be detected within 2 hours of corticosteroid exposure and some within 10 minutes .

Action:

Corticosteroids inhibit pro-inflammatory cytokine production, including that of interleukin-1 (IL-1), IL-2, the IL-2 receptor, interferon-a (IFN-a) , tumor necrosis factor (TNF) , and perhaps, various colony stimulating factors (CSFs) such as IL-3 . In addition, corticosteroids even in very low concentrations inhibit the synthesis of a variety of pro-inflammatory enzymes, including the macrophage products collagenase, elastase and plasminogen activator .

Lymphocyte proliferation in vitro, and delayed type hypersensitivity in vitro, are inhibited by corticosteroids

Large intravenous (i.v.) doses of corticosteroids given to normal human volunteers increase the numbers of circulating Neutrophils but decrease peripheral lymphocytes, eosinophils, and monocytes . Neutrophilia, for results from a combination of increased release of immature cells from the bone marrow, an increase in circulating half-life, reduced neutrophil egress from blood, and reduced vascular margination of cells.

Prednisolone is rapidly absorbed from the gastrointestinal tract and is reversibly bound to plasma proteins. Prednisolone is rapidly metabolized in the liver, conjugated and excreted in the urine. It disappears from the blood within 1.5–3 hours, having a half-life of about 1 hour. However, its action at the tissue level lasts considerably longer. Corticosteroids are perhaps the only drugs which reliably, effectively and rapidly suppress synovitis in rheumatoid arthritis (RA). This effect was demonstrated long before their mechanism of action was investigated and cannot be fully explained by the factors described above.

In a recent review of the main clinical trials of corticosteroids in RA it was concluded that in both short and long-term studies corticosteroids are effective anti-inflammatory agents, significantly better than placebo in the relief of pain and stiffness, and superior to nonsteroidal anti-inflammatory drugs (NSAIDs). However, benefits are not sustained unless increasingly high doses are employed, so that side effects and adrenal suppression preclude their long-term use in RA except in specific circumstances. Several studies appear to suggest that corticosteroids may possess disease-modifying properties. In a follow-up study of the original patient cohort of the early UK studies, the evidence suggested that over the first 4 years of treatment corticosteroids inhibited the development of erosions. There are also studies which support the contention that corticosteroids may be useful in improving or maintaining function.

There is no doubt that low doses of corticosteroids in dosages up to 10mg/day are effective anti-inflammatory agents. It is not clear, however, whether they do possess disease-modifying activity . Moreover, the use of oral low-dose corticosteroids as supplementary anti-inflammatory agents may be advocated because their side-effects profile is more acceptable than those of other immunosuppressive agents.

Low dose and trim thereafter when the second line agents start kicking in.
Never self dose...follow your doctors advice.
Avoid high doses unless the indications are present for these.
Respect it... Its a potent tablet...with significant side effects if abused.

Weaning Steroids in RA joint disease

My technique is different for different individuals. I don't believe that one should lower the dose in an uncompromising regimented fashion in the rheumatic diseases. Each person and their disease is different...

I avoid getting into the situation of mega-doses for my patients unless they have systemic organ disease involvement i.e. cardiac/pulmonary/vasculitis etc...
Therefore rule 1 - For joint disease.. I avoid doses >10 mg ....unless clinically required.

Once I am reducing down from 10mg, I reduce by 2.5 mg at a time - but slowly..
Each reduction is done in a stable clinical state , with the joints showing as little swelling as possible.
Nearly all my rheumatoid arthritis patients are on DMARDS - disease modifying antirheumatic drugs, which enable me to do this.

This may mean 1-3 months or more between reductions if so required.
i.e. on average
10mg/day 2 months
7.5 mg per day..
5 mg /day..
2.5mg per day...
Sometimes I even use an alternating dose i.e. ....7.5mg alternating with 5mg/day or 5 mg alternating with 2.5mg/day

Once I am at 2.5mg.. I start to go..
2.5mg alternate day..
2.5mg every 3rd day..
2.5mg every 4th day....etc, etc.

If at any stage the patient flares ---I go back to the previous level and retry from that level in a structured but individualized manner

The important thing is to ensure that whilst this is all happening, the disease itself is being controlled using DMARDS at a deeper level.

Steroids in psoriasis

These should generally be avoided if possible as there is a danger of withdrawal causing a flare of pustular psoriasis. However - I have found intra-articular steroids and soft tissue injections to be safe and effective.

Steroids in Systemic disease

A number of Rheumatic diseases require these drugs and usually in high doses.

Steroids in high doses are frequently required in a variety of life threatening problems seen in the rheumatic diseases. These in particular refer to conditions characterized by systemic organ involvement - in particular:

Rheumatoid arthritis.
Systemic Lupus erythematosus.
Scleroderma.
Polymyositis / dermatomyositis.
The vasculitidies...including polyarteritis nodosa / Wegeners granulomatosis / Giant cell arteritis.
Antiphospholipid antibody syndrome.

Commonly seen in these diseases are organ complications including:

Cardiac disease such as myocarditis and pericarditis.
Pulmonary disease such as pneumonitis or pulmonary interstitial disease and fibrosis.
Cerebral disease.
Hematological disease - such as haemolysis / thrombocytopenia (low platelet count).
Renal disease - including nephritis and nephrotic syndrome.
Vascular disease and vasculitis.

The method of treating is usually oral cortisone such as prednisone / Prednisolone, starting usually at a dose of up to 1mg / kg of body weight - depending on severity of disease.
The dose is then reduced depending on response and activity of disease.

A second method includes "pulse" therapy - where a dose of methyl Prednisolone is given - at a dose of 250 mg - 1 gram in a saline infusion over 30-60 minutes. The frequency of these pulses depends on the disease entity i.e. diagnosis and the severity of disease. A common method is to pulse daily for three days, and then possibly to use oral steroids. Alternatively, periodic pulse therapy can be given - and trials of monthly to three monthly pulses have been used for example in the nephritis of systemic lupus erythematosus.