Most chronic inflammatory rheumatic diseases are characterised by a ‘misdirection’ of the immune system. This results in a complex defence reaction against the body's own tissue, which should actually be directed against foreign organisms such as bacteria or viruses.
Since the better understanding of autoimmune diseases, therapeutic efforts have therefore always been made to ‘slow down’ the immune system in order to weaken the immune response and thus treat the respective clinical picture adequately. T-cells (or T-lymphocytes) play a central role in the immune response, acting as a kind of mediator between the cells that recognise the supposed foreign invader (antigen-presenting cells) and the monocytes and macrophages that are involved in the actual defence reaction.
Most of the substances listed here are aimed in one way or another at inhibiting or reducing T cells or lymphocytes in general, and also have other effects that slow down the immune system, while most biological DMARDs act very specifically on a particular cell type (e.g. B cells), molecule (e.g. abatacept) or cytokine (e.g. TNF).
Immunosuppressants are substances that, in contrast to DMARDs, have a broader area of application. They are frequently used for collagenoses and vasculitides, but also for other autoimmune diseases that do not belong to the rheumatic group and in transplantation medicine. Their main task is to inhibit the immune response. The most common immunosuppressants that are also used in rheumatology are listed below.
Cyclophosphamid
In terms of its chemical structure, cyclophosphamide is a nitrogen mustard gas compound. It has a cytostatic effect and causes the DNA of rapidly dividing cells in particular to break.
In rheumatology, lymphocytes and in particular T cells are the target cells that are depleted by the administration of cyclophosphamide. Cyclophosphamide is also a commonly used substance in the field of oncology.
Cyclophosphamide is used in rheumatology, particularly in SLE (especially in lupus nephritis), various vasculitides (especially Wegener's granulomatosis), less frequently in antiphospholipid antibody syndrome and in certain forms of systemic sclerosis.
Cyclophosphamide is administered either intravenously as bolus therapy at two-week intervals (so-called ‘Eurolupus’ regimen), at four-week intervals (NIH regimen) [JG1] or by mouth with daily doses of 1-2 mg/kg body weight.
In other diseases, such as Wegener's granulomatosis, an initial low-dose daily i.v. regimen can later be replaced by daily oral administration.
Cyclophosphamide is often administered in life-threatening conditions, which are usually started with an intravenous regimen. After approx. 10 to 14 days, the effect of the substance on the leukocytes is fully pronounced (so-called leukocyte nadir); however, this drop varies greatly from person to person, but in any case, even if there is clinical improvement, a blood count should be taken approx. 10 days after cyclophosphamide application in order to prevent possible massive leukopenia.
Infections should be ruled out from the very first application of cyclophosphamide or, if administration is unavoidable, they should be effectively treated and/or prevented with antimicrobials.
Due to the cytotoxicity of the substance, the occurrence of haemorrhagic cystitis and an increased incidence of carcinomas of the urinary bladder have also been observed, which is why intravenous administration should always be accompanied by mercaptoethanesulphonate sodium (mesna), which binds the toxic metabolites. Other side effects include mucositis, pancytopenia and alopecia. Due to its toxicity, a cumulative dose of more than 65 grams should be avoided if possible.
Azathioprin
Azathioprine is a so-called prodrug which, once absorbed, is rapidly converted into mercaptopurine and then into active intracellular thiopurine metabolites. These lead to an inhibition of the new synthesis of purine nucleotides and thus to a reduction in lymphocytes, especially T cells. This substance is widely used in transplantation medicine, although in recent years it has been increasingly replaced by other preparations such as mycophenolate mofetil (see below).
Azathioprine still plays an important role in rheumatology, particularly in collagenoses and especially in poly- and dermatositides, but it is also a common immunosuppressant in certain forms of SLE and vasculitides. The efficacy of azathioprine has also been demonstrated in cP, although it does not reach the high level of MTX.
It is taken once to three times a day, with a maximum daily dose of 2-3 mg/kg body weight, although this can be increased in exceptional cases.
As with most other DMARDs, laboratory monitoring should be very close, especially at the start of therapy. The most feared side effects are myelosuppression, transaminase elevations and pancreatitis are also observed.
At this point it is also important to point out that azathioprine should never be administered in combination with allopurinol, as this inhibits xanthine oxidase and subsequently massively increases the toxicity (especially myelosuppression) of azathioprine.
Mycophenolat Mofetil
In terms of its chemical structure, the substance mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid into which it is converted in the organism. This in turn is a selective, non-competitive and reversible inhibitor of inosine monophosphate dehydrogenase and inhibits the synthesis of guanine-containing nucleotides and thus T and B cell proliferation.
Mycophenolate mofetil is frequently used in transplantation medicine in combination with calcineurin inhibitors. In rheumatology, this drug plays a relatively minor role, but is becoming increasingly established as an alternative to other substances in various manifestations of SLE and other collagenoses.
It is taken once to three times a day and laboratory values, particularly blood counts, must be strictly monitored at the start of therapy, as pronounced leucopenia can occur, which makes it necessary to reduce the dose.
Side effects include diarrhoea, vomiting, anaemia and thrombocytopenia.
Calcineurin inhibitors
Also originating from the field of transplant medicine, cyclosporine in particular was also frequently used for a long time in inflammatory rheumatic diseases, but has been increasingly displaced in recent years, mainly due to its unfavourable side effect profile and the flood of newer, more efficient DMARDs and, with a few exceptions, no longer plays a major role today, so is only used in therapy-refractory cases or contraindications to other substances.
Calcineurin inhibitors are originally isolated from tubular fungi (cyclosporin) or streptomyces (tacrolimus and sirolimus) and, as the name suggests, lead to an inhibition of calcineurin. This subsequently induces a reduction in IL-2 and T-cell inhibition, thus suppressing the immune response. In addition to cyclosporin A, newer preparations such as tacrolimus and sirolimus are also used.
What the calcineurin inhibitors have in common is that they are metabolised very differently from person to person, which is why regular level checks are necessary and the daily dose can vary greatly. The main side effects are nephrotoxicity and hypertension, the intake schedule is two to three times a day and the intervals should be strictly adhered to due to the short half-life in order to avoid strong fluctuations in levels.
Kidney and liver function parameters and blood pressure should be checked regularly.