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Adverse skin reactions - more than just skin deep

Medical progress is a double-edged sword. Severe skin reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are caused by drugs that have originally been developed for the treatment or alleviation of other diseases. In some cases, the consumption of these drugs can be fatal. The Centre for Documentation of Severe Skin Reactions (dZh) in Freiburg has been collecting information on rare skin diseases for around 20 years. It is seen as important to set up a comprehensive Europe-wide documentation in order to find out which drugs can cause such diseases. Pharmaceutical companies are also interested in this information. However, it is uncertain for how much longer the dZh will be able to continue its international work. Although all the official authorities acknowledge the importance of the dZh’s work, no single organisation really feels responsible for providing basic funding.

Patient with Stevens-Johnson syndrome (SJS). © Dr. Thomas Habif

Life is difficult for people suffering from rare diseases. Pharmaceutical and medical research mainly focuses on common diseases and is less interested in treatment possibilities for rare diseases. Severe skin reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) affect one to two in a million people, which is why they are classified as rare diseases. These diseases result from incompatibility reactions of the skin to certain drugs.

SJS and TEN patients develop skin blisters, the epidermis becomes necrotic and separates from the dermis, in a similar way to second-degree burns. Painful swelling and haemorrhagic lesions appear in the mucous membranes, including in the mouth, eye conjunctiva or genital regions. SJS and TEN are independent of age and gender and can occur in any person with different degrees of severity. In addition, these diseases are totally unpredictable. "Although such skin reactions are rare, they are fatal in up to 50 per cent of people affected," said Dr. Maja Mockenhaupt, head of the Centre for Documentation of Severe Skin Reactions (dZh) and senior physician in the Department of Dermatology at the Freiburg University Medical Centre. It is therefore important to document all cases so that studies can be carried out to find answers to questions such as: which medications can cause the diseases? Is there a genetic predisposition to such diseases? Is treatment available?

The circle of suspects

Around twenty years ago, the Freiburg-based dZh began recording all SJS and TEN cases in Germany. “My former boss, Prof. Dr. Erwin Schöpf, dealt with allergic skin diseases,” recalls Mockenhaupt. “In the mid-80s, Schöpf worked with French colleagues to carry out retrospective studies after a connection between severe skin reactions and the consumption of the anti-rheumatic and pain-relieving drug isoxicam was discovered in French patients. The results of the study that gave evidence of the connection were published in 1990. In 1989, Prof. Schöpf was awarded a research grant from the former German Ministry of Research and Technology (BMFT, now BMBF), which enabled the dZh to be established at the Department of Dermatology at the Freiburg University Medical Centre. Schöpf’s team developed standardised questionnaires and began the search for contacts at hospitals that treated patients suffering from severe skin reactions. Once the contacts were established, a quarterly letter has been sent out ever since accompanied by a prepaid postcard requesting the contact persons to report suspected TEN or SJS cases. “Every time a clinic reported a TEN or SJS case, I would go and visit them to examine the patient and collect the data,” said Mockenhaupt. An independent board of experts was established to validate the diagnoses. Nowadays, TEN or SJS cases are usually reported by phone or email, but a dZh doctor still sees all such patients in German hospitals. The dZh has received more than 6,000 notifications of which around 2,500 have been classified as TEN or SJS. The dZh database is the largest severe skin reaction database in the world.

The information stored in the database helps doctors to carry out so-called case control studies in which SJS and TEN patients are compared with healthy people of matching age and gender. Which medications are taken by the SJS and TEN patients? Using statistical methods, Mockenhaupt and her colleagues were able to determine the medications that posed the greatest risk of provoking the skin diseases. “Around 60 per cent of all cases are the result of a handful of drugs,” said Mockenhaupt going on to add “we call these drugs ’highly suspect causative agents’”. The drugs include medications for the treatment of chronic gout (allopurinol), antibacterial sulfonamides, certain anti-epileptic drugs (for example carbomazepin), non-steroidal anti-rheumatic drugs of the oxicam type (for example piroxicam) or nevirapin (a drug for the treatment of AIDS). Another 15 per cent of all TEN and SJS patients develop the disease as a result of ’suspect’ causative agents (for example, a range of antibiotics or pain relievers). No clear causative agent could be determined for the remainder of cases nor were the cases associated with infections (for example mycoplasma infections). “On the other hand, we were also able to exclude a number of medications as the cause for TEN or SJS,” said Mockenhaupt naming drugs such as ibuprofen, insulin or antihypertensives as examples. “And this is good news.” The results of the study were also used to develop an algorithm that is used to calculate the most probable cause of a skin reaction.

An uncertain future

In September 2010, the dZh celebrated its 20th anniversary with an international symposium in Freiburg. © dZh

The case control studies were carried out in cooperation with international partners. The project, called SCAR (an acronym for "severe cutaneous adverse reactions"), was carried out in cooperation with groups from France, Italy, Portugal and the USA and was terminated in 1996. In 1997, the dZh started a follow-up project (EuroSCAR) that involved partners from Germany, Italy, France, the Netherlands, Israel and Austria. In the time that had elapsed since the first project, new medications had entered the market. Data were collected up until 2001. In 2002, the dZh started RegiSCAR (Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples), which also involved partners from Taiwan, South Africa and England. In addition to systematically collecting data using questionnaires, the dZh and the RegiSCAR partners also established a blood bank with patients' blood samples. Six clinical groups and one genetic group participated in the establishment of the blood bank and the geneticists were able to identify a genetic disposition for TEN and SJS and determine a region on one of the human chromosomes that is responsible for people developing TEN and SJS. In addition, progress studies involving SJS and TEN survivors were carried out and showed that many of the patients suffered from long-term and severe secondary damage, in particular of the skin and mucosa. Many patients displayed severe eye reactions. Adults and children alike suffer from extremely dry eyes, ingrown eyelashes and agglutinations. "Therefore, SJS and TEN are not only life-threatening diseases, but must also be seen as chronic diseases," said Mockenhaupt. RegiSCAR was partially financed with EU grants, but financing came to an end in 2005.

"Our major problem is that we mainly receive funding for concrete projects," said Mockenhaupt. "We are mainly supported by pharmaceutical companies for specific projects related to drug safety that are of a short duration." The acquisition of data, the maintenance of the blood sample bank, the cooperation with the doctors who report suspect cases and treat patients with severe skin reactions needs to be continued independently from concrete projects. Mockenhaupt has a full-time senior physician post at the Department of Dermatology, and she works for the dZh during her free time. Three of her colleagues and some temporary employees are financed with third-party funds. The dZh work requires basic funding, but neither the EU, the German Ministry of Education and Research (BMBF) nor authorities that use dZh data such as the Federal Institute for Drugs and Medical Devices (BfArM) feel responsible for this. "This will not be viable for much longer," said Mockenhaupt. Funding programmes for research into rare diseases have been available for some years now, but they are restricted to research into monogenetic syndromes caused by a single defective gene. Skin diseases such as TEN and SJS have a genetic component, but are triggered from the outside, namely by drugs. And it would appear that no money is available for this type of investigations.

Further information:
PD Dr. Maja Mockenhaupt
Centre for Documentation of Severe Skin Reactions (dZh)
Department of Dermatology
Freiburg University Medical Centre
Hauptstr. 7
D-79104 Freiburg
Tel.: +49 761 270-6723
Fax: +49 761 270-6834
E-mail: dz(at)uniklinik-freiburg.de

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