Single Blind Randomized Controlled Trial of ‘Azathioprine Versus Corticosteroids in Parthenium Hysterophorus Induced Contact Dermatitis

Aims

Materials and methods

Inclusion criteria

Exclusion criteria

Randomization procedure

Chasrt 1: Age distribution.

Agriculturists were the maximum affected (64.7%), followed by manual laborers and house wives. All the patients were from various districts of Karnataka state, most of them from Davangere (12 patients, i.e., 35.3%), where Parthenium is rampant. 16 patients (47%) complained of aggravation in summer, followed by 5 patients (14.7%) who had aggravation in winter.

Twenty-eight patients (82.4%) gave history of direct contact with the plant. Thirty-two (94.1%) had history of exacerbations and remissions. A very significant number of patients (32, i.e., 94.1%) gave history of photo aggravation. Two patients (5.9%) had atopic background in the form of allergic rhinitis and family history of asthma. The most common associated disorders observed were diabetes mellitus in 6 (17.65%) and hypertension in 5 (14.7%). There were 12 smokers, 8 people who consumed alcohol and 4 betel nut chewers, but none attributed their aggravation to their habits. Previous treatment modalities: Majority were treated with topical steroids. (28 patients, i.e., 82.4%), antihistamines (67.7%) and systemic steroids (41.2%). Other modalities included emollients, azathioprine, ayurvedic and homeopathic medicines, sunscreens and hydroxychloroquine.

The most common pattern of presentation in this study was that of ABCD type in 31 patients (91.2%) involving photoexposed areas plus eyelids, ear creases, naso-labial folds, retro-auricular area, cubital and popliteal fossae.

Other presentations included photo dermatitis in 3 patients, Actinic reticuloid in 2 and hand dermatitis in one (Table 1).

Table 1: Pattern of dermatitis.

Extent of involvement

Treatment

Table 3: Percentage of reduction in DASI after treatment in Azathioprine group.

Side effects

Statistical analysis

Parthenium dermatitis is now rampant in India, especially in pockets in the north and southwest. It usually affects adult males, earlier studies showing a male: female incidence of 4.55:1 [7]. Our study showed a ratio of 7.5:1, probably because women tend to remain indoors more often, reducing the risk for exposure and sensitization. The influence of age in the study was striking, the maximum number of affected cases being in the group of 41-60 years, unlike other studies which observed 30-39 years[7]. The duration of the disease in this study ranged from 6 months to 20 years which shows the chronic nature of Parthenium dermatitis. Majority of the affected patients were invariably exposed to the allergen most of the times and the severity of the dermatitis depends not only on irritant or allergic potential of the plant, but also on degree of exposure and individual sensitivity. The principle source of exposure was direct contact with the living plant. The plant hairs (trichromes) contain surplus of dermatitis producing sesquiterpene lactones. The airborne pollen also contains the oleoresin leading to ABCD. The plants crumble during summer season to a finely scattered dust, which virtually fills the surrounding atmosphere and forms another source of ABCD [8]. Lack of sun protection, working and hygienic habits may also contribute to chronicity of the disease. Clothes dried outside in sun may also act as a potential trap for airborne Parthenium allergens and on sweating the allergens leach out on to the skin to produce a chronic recurrent dermatitis. One of our patients had onset of dermatitis following wearing a shirt which was kept to dry in open air on a Parthenium plant.

Most complain exacerbation in summer, may be due to sweating as well as photosensitive nature of the plant. Photo contact dermatitis to Parthenium has been reported earlier [9], but we were unable to prove it as the Parthenium antigen showed equal reactions on irradiated as well as non-irradiated sites on photo patch testing (unpublished observation). Exposure to airborne plant allergens may first cause ABCD which mimics photo dermatitis, but subsequently develop true photo dermatitis like Chronic Actinic Dermatitis (CAD) or Actinic Reticuloid (AR) syndrome.

Earlier studies have shown that reduction of MED to UVB is a definite indicator of photosensitivity in Parthenium dermatitis [10]. It is possible that retention of photo allergen at site of repetitive photoallergic reactions can cause classic photo allergic reactions with photo antigen trapped in the skin; the reactions lasting for months to years. Majority of our patients were middle to old aged, hence explaining the long term influences of the allergen.

Major aggravating factors in this study were the 3 ‘S’s - sunlight, summer and sweating. 82.2% had direct contact with the plant during their work, and the rest may have developed the disease due to the air borne nature of Parthenium dermatitis.

The various patterns of dermatitis we observed were airborne contact dermatitis, photo dermatitis, hand dermatitis, lichenoid and chronic actinic reticuloid pattern.

Frequent concurrence of atopic dermatitis with Compositae dermatitis has been reported in some earlier studies [11], but not in our study. Increased incidence of Parthenium dermatitis in atopics may be due to the chronically irritated and damaged skin which makes them susceptible to sensitization of any nature.

The efficacy of Azathioprine in Parthenium dermatitis has been shown earlier, so also its relapsing tendency on stopping medication [6,12]. Azathioprine is a 6-Mercaptopurine analogue which acts by interfering with DNA and RNA synthesis and repair. It has a greater effect on T cells than B cells, and also on Langerhans cells, NK cells and monocytes. Azathioprine inhibits the effector phase of immune response, but not the induction phase. The adverse effects include nausea, vomiting, diarrhea, abdominal pain, pancytopenia, hepatotoxicity, pancreatitis, polyneuropathy, drug rash and fever, as well as increased incidence of malignancies, especially in transplant patients on long term treatment.

In the present study, a large number of drop outs (58.8%) in the Azathioprine group may be due to the delay in onset of action and poor control of itch. We were unable to contact the dropouts and enquire the exact reason for the same. Though corticosteroids act faster, Azathioprine has a ‘steroid sparing effect’ leading to lower dosage of steroids and thus a lesser risk of serious steroid induced adverse effects while maintaining an adequate immunosuppressive effect.

In our study, prednisolone group generally had good initial improvement, but there was no long lasting remission whereas Azathioprine group had relatively better stable disease free period ranging from 2 to 15 months after stopping the drug. The non significance of p-value may be due to the higher number of dropouts in the Azathioprine group. The shorter duration of steroid schedule was safe enough to avoid serious side effects but not adequate enough for prolonged control of the dermatitis. Relapsed patients who were started on oral mini pulse steroid therapy (betamethasone 6 mg weekly once or twice) responded very well with longer remissions and least number of side effects.

The medical management of Parthenium dermatitis will be useless unless the patient is seriously motivated for proper preventive measures. The most effective treatment would be to fully remove the patient from Parthenium infested areas, but as this is impractical in most cases, we need to focus on other points like removal of plant from the patient’s environment as far as possible, frequent washing of exposed areas with soap and water before the antigen penetrates the skin, use of barrier cream, frequent changes and washing of used clothes, limiting sun exposure, drying of washed clothes indoors etc. We are also attempting to devise an acceptable mask to be worn by severely affected people when out in the open.

The statistical significance to confirm the superiority of either of the drugs in terms of improvement in DASI, itch and sleep was undermined by the large number of dropouts in the Azathioprine group, which clinically had an edge over the prednisolone group in terms of prolonged remission. Clinically the beneficial effects of Azathioprine were very obvious, with a progressively steady rise in improvement of scores in all assessment parameters, a stable post treatment period and a better patient compliance. Prednisolone, on the other hand, demonstrated a quicker onset of action, but a quicker relapse as well.

We would like to conclude that Azathioprine gives lasting results, a stable prolonged relapse free period and is suitable for a chronic problem like Parthenium dermatitis, but has to be used with caution with proper monitoring. It is imperative that the patients be counselled regarding the nature of their condition, the slow onset of action of azathioprine and the need for lifestyle changes and proper medication and photoprotection. Prednisolone is ideal for acute severe flare ups as a short course therapy, with an early withdrawal for avoiding the associated morbidities.

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