Tag Archives: azathioprine

The clinical and epidemiological features of pemphigus vulgaris (PV) are well documented but there remain few reports of oesophageal involvement of PV. Although previously considered to be rare, recent reports have suggested that up to 87% of patients with PV may have symptoms, or endoscopic features, of oesophageal disease that may be poorly responsive to conventional corticosteroid-sparing immunosuppression.

The present report details the clinical and immunological features of a 53 year old Asian female who developed symptoms and signs of oesophageal PV during therapy with azathioprine and decreasing prednisolone dosage. Oesophageal involvement occurred during stable oral disease.

Oesophageal involvement can occur without significant oro-cutaneous lesions and immunological evidence of PV. This suggests that immunological targets for oesophageal disease may differ from those of other mucocutaneous areas, and that conventional first-line systemic therapy may not be effective for oesophageal lesions.

Full article available at: http://www.ingentaconnect.com/content/ubpl/wlmj/2012/00000004/00000002/art00001

A 14-year-old male presented with seven years history of recurrent episodes of fluid filled, itchy and eroded lesions over the body not responding to oral corticosteroids and azathioprine. Dermatological examination revealed crusted plaques and erosions in a seborrheic distribution. Histopathology of skin lesions and direct immunofluorescence were characteristic of pemphigus foliaceus. He was treated with dexamethasone pulse therapy with inadequate response. However, relapsing skin lesions revealed a circinate arrangement with a predilection to trunk and flexures. In view of clinical features suggestive of IgA pemphigus, he was started on dapsone, to which he responded dramatically in four weeks. However, repeat biopsy continued to reveal features of pemphigus foliaceus and ELISA for anti- desmoglein 1 antibodies was positive.

Background  The classic treatment for pemphigus vulgaris is prednisolone. Immunosuppressive drugs can be used in association.

Objective  To compare the efficacy of Azathioprine in reducing the Disease Activity Index (DAI).

Patients and methods  A double blind randomized controlled study was conducted on 56 new patients, assigned to two therapeutic groups: (i) prednisolone plus placebo; (ii) prednisolone plus Azathioprine. Patients were checked regularly for 1 year. ‘Complete remission’ was defined as healing of all lesions after 12 months, and prednisolone <7.5 mg daily, (DAI ≤ 1). Analysis was done by ‘Intention To Treat’ (ITT) and ‘Treatment Completed Analysis’ (TCA).

Results  Both groups were similar in age, gender, disease duration, and DAI. Primary endpoint: By ITT and TCA, the mean DAI improved in both groups with no significant difference between them. The difference became significant for the last trimester (3 months; ITT:P = 0.033, TCA: P = 0.045). Secondary endpoint: The total steroid dose decreased significantly in both groups, with no significant difference between them, except for the last trimester (ITT: P = 0.011, TCA: P = 0.035). The mean daily steroid dose decreased gradually in both groups becoming statistically significant in favour of azathioprine, in the last trimester, especially at 12th months (ITT: P = 0.002, TCA:P = 0.005). Complete remission was significant at 12 months only for TCA (AZA/Control: 53.6%/39.9%, P = 0.043).

Limitations  Sample size was rather small to demonstrate all differences. Other limitations include the choice of primary and secondary endpoints and the unavailability to measure thiopurine methyltransferase activity.

Conclusion  Azathioprine helps to reduce prednisolone dose in long-run.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-3083.2012.04717.x/abstract;jsessionid=4F8C646E8902BB54AC0026B542EF91FD.d03t01

We report a case of neutropenic ulceration in a 42-year-old woman receiving azathioprine for pemphigus vulgaris. She developed multiple indolent ulcers involving the nose, neck, and back, after about 6-8 weeks following commencement of azathioprine 50 mg daily. The ulcers were large, disfiguring, dry, and with basal necrotic slough. They were painless and did not discharge pus. The absolute neutrophil count was severely depressed initially, but normalized following azathioprine withdrawal. Swab culture revealed colonization with Klebsiella pneumoniae and the ulcers healed with local debridement, treatment with imipenem, and topical application of mupirocin. However, nasal disfigurement persisted. Neutropenic ulceration is known to be associated with azathioprine therapy but we report this case because of the unusual presentation-indolent cutaneous ulcers. Early recognition of the problem and drug withdrawal can prevent complications like disfigurement.

Neutropenia is characterized by an abnormally low number of neutrophils in the blood. Neutrophils normally comprise 45-75% of circulating white blood cells, and neutropenia is diagnosed when the absolute neutrophil count falls to <1500/ μL. Slowly developing neutropenia often goes undetected and is generally discovered when the patient develops sepsis or localized infections.

There are many causes of neutropenia, and immunosuppressants are a common iatrogenic cause. Azathioprine is an immunosuppressant drug that is being used for nearly 50 years now in organ transplantation and in diseases with suspected autoimmune etiology. Dermatologists use azathioprine as a steroid-sparing agent in various dermatoses such as psoriasis, immunobullous diseases, photodermatoses, and eczematous disorders. [1] The drug has been used in ulcerative autoimmune disorders such as Crohn’s disease and pyoderma gangrenosum. On the other hand, it has also been implicated as a cause of ulceration associated with neutropenia. [2] Most reports of neutropenic ulceration document involvement of the buccal mucosa and oral cavity.  We report a case of multiple severe cutaneous ulcers associated with long-term azathioprine use in a patient with pemphigus vulgaris.

Full article available at: http://www.ijp-online.com/article.asp?issn=0253-7613;year=2012;volume=44;issue=5;spage=646;epage=648;aulast=Laha

Although there are no standard guidelines for the treatment of autoimmune blistering diseases, azathioprine has shown good efficacy in acquired autoimmune blistering diseases, and is well tolerated. Side effects of azathioprine normally occur in mild variants. Severe reactions are due to reduced thiopurine S-methyltransferase (TPMT) or inosine triphosphate pyrophosphohydrolase (ITPA) activity. Therefore, screening for TPMT activity should be conducted in white patients and Africans, whereas Japanese should be screened for ITPA activity before therapy with azathioprine is started. Azathioprine is clinically meaningful for the treatment of pemphigus. (Source: Immunology and Allergy Clinics of North America)

http://www.immunology.theclinics.com/article/PIIS0889856112000240/abstract?rss=yes

By Nonhlanhla Khumalo, Dedee Murrell, Fenella Wojnarowska & Gudula Kirtschig
Archives of Dermatology March 2002 Vol 138 pages 385-389.
www.archdermatol.com

This review is different from the usual type of review you might read about bullous diseases in that by being “systematic” it was submitted ahead of time to an independent panel of editors at the Cochrane Collaboration for Evidence-Based Medicine stating that the aim was to summarize data from randomized controlled trials (RCTs) only for the treatment of BP. In addition, how those trials are to be searched for, analyzed and compared is scrutinized.

Out of all the databases only 6 RCTs were published, including 293 patients. One trial compared prednisolone at different doses: 0.75mg/ kg/day vs 1.25mg;/kg/day, and another compared methylprednisolone with prednisolone, and neither study found a significant difference between the two groups, but the patients on the higher prednisolone doses had more severe side effects.

By Dr. Pan Meng

Pemphigus is a group of organ-specific autoimmune disorders, including pemphigus vulgaris (PV), pemphigus foliaceus (PF) and paraneoplastic pemphigus (PNP). PV is the most common disease and represents this kind of potentially life-threatening disease. It is characterized by development of blisters and erosions on skin and mucous membranes, termed acantholysis.

In China, the number of the patients with PF and PNP are lower than that of PV, perhaps because of the limitation of diagnostic methods. We only diagnose these disorders by clinical symptoms, histopathology and immuno-fluorescense. In our hospital, from 1989 to present, we have detected 32 patients with pemphigus. Among them, 28 patients were diagnosed as PV and 4 patients were PF. We found PV often occurs in middle-aged people. In two older patients, potential tumors were accompanying. Now, with the development of immunology and molecular biology, the different autoantigen in every patient can be detected. Therefore, we can redetect the patients by ELISA.

Although pemphigus is a rare disease and its incidence in China is about 0.5-3.2 per one hundred thousand people, its impact on patients is devastating. In the past, the mortality of this disease was very high and many patients died within one to two years after diagnosis. At present, with the discovery and development of glucocorticoids, for example, prednisone, patients survive. But an important problem has emerged — the side effects of this drug. After a period of taking the drug, many patients suffer from infection, higher blood pressure, diabetes and osteoporosis. Some patients died, not from the disease itself, but from the side effects of prednisone.

Therefore, how do we treat patients correctly and how do we decrease the mortality rate? We have found the combination of glucocorticoids and immunosuppressives is the best method. In the acute stage, glucocorticoids are used to control the symptoms. Then, immunosuppressives are added to avoid the rebounding when the dosage of prednisone is decreased. The most common immunosuppressives are Azathioprine, Methotrexate and Cyclophosphamide.

Also, many Chinese traditional medicines play an important role, not only in the treatment of this disease, but in alleviating the side effects of the drugs. In the theory of Chinese Medicine, the excessive heart-fire and spleen wetness-evil are the main factors of pemphigus. When they spread to the skin, pemphigus will happen. So the rule in Chinese medicine in the acute stage is to clear away heat, eliminate wetness-evil and detoxify. In the chronic stage, it is to invigorate the spleen.

In the acute stage, blisters and erosions develop on the skin and mucous membrane. Patients show red tongue with thin white fur and string-like pulse on examination by the practitioner. With the differentiation of symptoms and signs, evils of wetness stagnating within the body and the heat-evil attacking the blood were confirmed. The principal includes four parts: clear away heat, eliminate wetness, detoxify and cool the blood. The names of the main herbal medicines used: (1) Clear away heat: Long Dan Cao, Huang Chen, Bai Mao Geng, Shang Shi Gao, Zhi Mu, Da Qing Ye, Bai Hua She She Cao, etc.; (2) Eliminate wetness: Ku Sheng, Che Qian Cao, Fu Ling Pi, Sheng Yi Mi, etc.; (3) Detoxify: Liu Yi San, DA Qing Ye, Lian Qiao, etc.; (4) Cool the blood: Sheng Di, Dan Pi, Chi Shao. The typical prescription is Long Dan Cao 10g, Huang Chen 10g, Bai Mao Geng 15g, Sheng Di 15g, Sheng Shi Gao 20g, Zhi Mu 10g, Liu Yi San 30g, Fu Ling Pi 10g, Sheng Yi Mi 30g, Di Fu Zi 20g, Bai Hua She She Cao 30g. It is concocted in water for oral doses, and can also be used on the lesion directly.

In the chronic stage, lesions become dry and erosions are cured. Patients feel itching on the skin. The signs of the tongue, the fur and the pulse become better than before. The main treatment is adding some other herbal medicine to alleviate itching, for example, Di Fu Zi, Bai Xian Pi, She Chuang Zi, etc. The typical prescription is Long Dan Cao 15g, Huang Chen 10g, Bai Mao Geng 20g, Sheng Di 15g, Liu Yi San 30g, Da Qing Ye 30g, Dan Pi 15g, Dong Gua Pi 20g, Ze Xie 15g, Zhu Ling 30g, Fu Ling Pi 30g, Sheng Mi Ren 30g, Ku Sheng 15g, Di Fu Zi 25g, Bai Hua She She Cao 30g, Chuan Cao Xian 15g, Bai Xian Pi 20g, Sheng Bai Shu 10g, Ma Chi Jian 30g.

We must point out that the treatment of Chinese tranditional medicine is an accessorial treatment in this severe disease. Its function is to reduce the dosage of the drugs and to facilitate the decrease of the drugs, further to decrease the side effects of the drugs. Besides these herbal medicines, many Chinese medicines also can be used to increase the immune system of the patients. For example, Lei Gong Teng, An Beng Feng, Lu Qui, and so on.

The goal of therapy is not to continue all medical treatment, but to improve the patients' quality of life. I hope traditional Chinese medicine will be of some benefit in achieving this goal.

By Jean-Claude Bystryn, M.D.
Professor of Dermatology
Director of Immunofluorescence Laboratory
The Ronald O. Perelman
Department of Dermatology
New York University Medical Center

Pemphigus vulgaris (PV) can enter into remissions in which all manifestations of the disease disappear and all therapy can be discontinued. How often, and when this occurs is unclear. Review of all major studies of PV conducted during the past four decades describes remissions as occurring in less than one-third of patients.1 However, a problem with these studies is that the incidence of remissions is usually provided at only a single time point. Thus, it is unclear how long it takes for remissions to appear, how long they last and what happens when therapy is discontinued. Further complicating interpretations of the results is that the meaning of remission is often unclear. The criteria used by different investigators to define this event differ and/or are not provided. The practical outcome of this incomplete information is uncertainty about the management of pemphigus. It is unclear whether treatment simply suppresses the manifestations of the disease and must be continued permanently, or whether complete and durable remissions can be induced that permit therapy to be safely discontinued.