Psoriatic erythroderma and hypothalamus-pituitary axis suppression due to misuse of systemic steroid: two challenging cases.

Adding corticosteroid in homeopathic pills, self medication of steroid in the backdrop permanent cure in cases of psoriasis is not very uncommon in clinical practice in Indian subcontinent. First case a 52 year man, a known case of psoriasis vulgaris with psoriatic arthropathy of 15 years duration received multiple modalities of therapies without any satisfactory response. He was on self medication of tab prednisolone 10 mg daily with Cushingoid features. Second case a 22 year old boy, a known case of psoriasis from last 06 years was on Homeopathic treatment with Cushinoid features. Tapering of systemic steroid in first case and discontinuation of homeopathic drug in second case resulted in erythroderma and features of adrenal insufficiiency. Investigation revealed low morning cortisol and low cortisol following ACTH stimulation suggestive of HPA axis suppression. Planned withdrawal of steroid under the cover of short acting systemic steroid for short duration along with combination of immunosuppressants and supportive care gave an excellent result in both the cases.

What was known?

Long term application of topical corticosteroids in cases of psoriasis has resulted in HPA axis suppression.

Introduction

Erythroderma due to psoriasis is a difficult condition to manage; comorbidity of Hypothalamic-pituitary-adrenal (HPA) axis suppression poses an additional challenge in the management of erythroderma. Relapsing nature of psoriasis, compel many non-counseled patients to take treatments from alternative medicine (homeopathic, ayurvedic, unani etc), self-medication, because of their false belief, promises and assurance of permanent cure. Over-the-counter availability of oral and topical corticosteroid is known in South East and Middle East countries mainly in India, Pakistan, Nepal, Bangladesh, Srilanka, Thailand, Iraq and Iran, which makes people become easy prey to the adverse effects of these products. There are various cases reported, describing different topical forms of corticosteroid causing suppression of HPA axis.[12345] There are many reports of topical corticosteroid used in psoriasis leading to iatrogenic Cushing's syndrome.[678910] Even the report of Cushing's syndrome with herbal remedy containing betamethasone is found in the literature.[11] However, to our knowledge self-medication of systemic corticosteroid or homeopathic pills containing betamethasone in psoriasis leading to cushingoid features and suppression of HPA axis is nil. We report two such cases where withdrawal of corticosteroid leads to erythroderma, which were successfully managed in a tertiary care center.

Case Reports

Case 1

A 52-year-man, a known case of psoriasis vulgaris with psoriatic arthropathy of 15 years, who had received many therapies including systemic methotrexate, psoralen plus ultraviolet rays exposure (PUVA), acitretin, cap cyclosporine, leflunamide, mycofenolate mofetil along with topical corticosteroid and salicylic acid combination without satisfactory outcome. Infliximab and aciretin could not be tolerated by the patient. He was on self-medication of tab prednisolone 10 mg from last 10 years in a false belief of permanent cure. During the course of disease, he was managed for esophageal candidiasis, generalized molluscum contagiosum, high blood sugar and hypertension. Tapering of prednisolone twice resulted in severe pustular erythroderma, thus it was not attempted again by the treating dermatologist.

On presentation, he was on methotreaxte 12.5 mg/week, leflunamide 25 mg once daily, tab prednisolone 10 mg, topical steroid and emollient along with two drugs antihypertensive and oral hypoglycemic.

General examination revealed height of 170 cm with weight of 86 kg with body mass index of 29.75 kg/m2 and BP of 146/100 mm of Hg. Cushingoid features was noted in the form of moon face, central obesity, thin extremities, bowing of knees and thin atrophic skin with multiple prominent superficial vein on the trunk along with proximal muscle weakness in all four extremities with power of grade 3/5. Multiple, psoriatic plaques were present on the trunk and all four extremities sparing face, genitalia, palms and soles. There were multiple molluscum contagisum on the face. There were deformities of small joints of hand and feet.

Investigations revealed Hb - 9.4 g/dl, blood sugar F - 152 mg/dl and PP - 218 mg/dl; Chest X-ray PA view - cardiomegaly and ECG - sinus tachycardia. Initial endocrinological tests revealed, morning fasting plasma cortisol level of 0.8 μg/dL (normal 5-7 μg/dL) and 24-hour urinary free cortisol levels less than 4 μg/24 h. Adrenocorticotropic hormone (ACTH) stimulation test performed after three days with administration of ACTH in dosage of 250 μg, and cortisol levels were measured at 0, 30, and 60 minutes, which was 3.2 μg/dL, 4.5 μg/dL and 7.2 μg/dL, respectively (normal > 18 mg ⁄ dL after 60 minutes). Results revealed HPA axis suppression.

His oral steroid was tapered from the 10 mg to 5 mg over a period of 07 days. However, within three days of 5 mg prednisolone he developed flare of erstwhile psoriasis with severe debilitating arthropathy. He became febrile with temperature of 102 F, tachycardia of 126/min, developed hypotension with BP of 94/58 mm of Hg, lethargy and severe weakness. There was multiple, confluent, erythematous plaques studded with multiple tiny pustules covering more than ninety percent body surface area. Involvement of flexural areas had caused maceration and foul smell [Figure 1]. There was severe restriction in the movement of small joints of hands and foot as well as larger joints.

Figure 1

(a) Erythema and scaling of trunk and extremities with maceration of axilla. (b) Erythema and scaling involving entire back. (c) Maceration and erosions of groin. (d) Tiny pustular lesion on erythematous plaques with swelling of feet and deformed joints

He was managed in ICU set up with ambient temperature of 32°C, high protein diet (3 g/kg/day), IV antibiotic (ticarcillin with salbactam), injection hydrocortisone 50 mg 12 hourly, injection etarnacept 50 mg subcutaneous (SC)/weekly along with bland emollient. Investigation revealed Hb of 8.4 g/dl, total leucocyte count (TLC) 21000/cmm, with polymorph predominance; with blood sugar in the normal range. His antihypertensive and oral hypoglycemic were withdrawn. His prednisolones 5 mg, methotrexate 12.5 mg/week were continued. Cap cyclosporine was added in the dose of 5 mg/kg body weight. His hypotension and tachycardia settled over the next three days. Injection hydrocortisone was stopped. His pustular lesion started regressing, so cyclosporine, systemic antibiotic were stopped after 07 days. Gradually, his antihypertensive and oral hypoglycemics were restored. His follow-up TLC became normal.

His psoriatic lesions along with psoriatic arthropathy have shown significant regression over 02 months [Figure 2]. His prednisolone was gradually tapered and stopped over one and half months. There has been no flare of psoriasis as well as arthropathy since last admission. He is maintained on injection methotrexate 7.5 mg/week and 25 mg eternacept SC/weekly with supportive bland emollient.

Figure 2

(a) Erythema and scaling with striae on the left shoulder and chest. (b) Erythema and scaling with striae on the right shoulder and chest. (c) Erythema and scaling with superficial lakes of pus on the back

Case 2

A 22-year-old boy, a known case of psoriasis since 06 years, was on homeopathic treatment from last 04 yrs. He presented with sudden onset of generalized redness and scaling of body for seven days duration after he discontinued the homeopathic treatment. Initial general examination revealed his weight of 88 kg, height of 168 cm with body mass index of 31.20 kg/m2. He was febrile with temperature of 102°F, tachycardia of 124/minute regular and was hypotensive with blood pressure of 90/60 mm of Hg. He also had cushingoid features along with proximal muscle weakness in all four extremities with power of grade 4/5. Dermatological examination revealed pustular erythroderma [Figure 3].

Figure 3

(a) Post-treatment marked improvement in erythema and scaling of back. (b) Post-treatment marked improvement in erythema and scaling of lower limbs

Initial investigation revealed Hb 11.2 g/dl, TLC 17300/cmm with polymorphic lymphocytosis. Morning plasma cortisol level was 0.7 μg/dL and 24-hour urinary free cortisol levels was less than 4 μg/24 h. Cortisol level was 6.8 μg/dL following 60 minutes of ACTH stimulation with 250 μg. Results were suggestive of HPA axis suppression.

He was also managed in the ICU with similar supportive measures and cap acitretin 25 mg OD, cap cyclosporine 100 mg TDS along with supportive topical bland emollient. His homeopathic drug was analyzed and was found to be having betamethasone equivalent to 1mg per dose. He did not tolerate cap acitretin. Cap cyclosporine was discontinued due to very high BP. Finally, he was administered oral methotrexate with which he has shown good response. He was also given physiological dose of oral prednisolone in the dose of 5 mg daily which gradually tapered and stopped over one month. His erythroderma regressed totally over 21 days of hospitalization [Figure 4]. His follow-up investigations including morning serum cortisol become normal after two months.

Figure 4

(a) Post-treatment marked resolution of erythema and scaling of chest, abdomen and extremities. (b) Post-treatment marked resolution of erythema and scaling of back

Discussion

Exogenous glucocorticoids have a suppressive effect on hypothalamic corticotropin-releasing hormone and pituitary ACTH. Prolonged use of corticosteroids suppress the HPA and cause adrenal insufficiency by adrenal glands atrophy which take months to recover fully even after discontinuation of exogenous glucocorticoids. The increased level of glucocorticoids in the blood i.e. hypercorticism (iatrogenic Cushing syndrome) manifest classically as hypertension, diabetes, anxiety or irritability, facio-troncular obesity, buffalo neck, hirsutism, fragile skin, pink striae and telangiectasia.[12]

The status of HPA axis can be assessed with following tests: (i) basal plasma cortisol level i.e. morning fasting cortisol sampled between 7.30 and 8.30 am (normal 5-7 μg/dL) (ii) 24-h urinary corticosteroids level (free cortisol and 17-hydroxycorticosteroid) (iii) and plasma cortisol level sampled immediately before 30 and 60 mins following stimulation with 250 μg intravenous injection of Synacthen® (cosyntropin or ACTH)/(Synacthen® stimulation test) (normal 18-20 μg/dL). Synacthen® stimulation test is considered as the gold standard to assess HPA axis.[13]

Withdrawal of steroid in a patient of psoriasis on long term corticosteroid is known to rebound with pustular erythroderma.[14] In a case report by Campbell et al.,[10] a 9-year-old Mexican-American girl developed HPA axis suppression following application of medium strength topical glucocorticoid to large areas of her body surface for one month. Control of her skin disease required systemic therapy using cyclosporine and etanercept. Temporary supplementation with an oral glucocorticoid replacement was required to prevent potential life-threatening complications. In a report of Saeki H et al., a 4-year-old girl developed pustular psoriasis when she stopped topical corticosteroid which was managed by supplementing with short-term systemic corticosteroid and topical tacalcitol.[8]

Such steroid dependent patients require withdrawal plan and management of pustular erythroderma aggressively by combination of suitable immunosuppressant. While withdrawing corticosteroid, two principle goals should be borne in mind. Firstly, patients should receive lowest possible steroid dose (or complete discontinuation of therapy) in order to avoid long-term adverse effects. Secondly, potential consequences of adrenal insuffciency should be avoided by gradually reducing the glucocorticoid from supraphysiologic to physiologic doses. The physiologic dose is approximately 5 to 7.5 mg a day of prednisone, 15 to 20 mg a day of hydrocortisone, or the equivalent. During this phase of withdrawal patients are not at risk for adrenal insuffciency, nor do most experience symptoms of withdrawal syndrome. Therefore, the greatest concern at this time will be exacerbation of underlying disease. This switch may allow more opportunity to the HPA axis to recover.[121315] For the same reason, we have given tab prednisolone 5 mg alternate-day for one month before we finally stopped it in the first case.

The combination of etanercept with methotrexate (MTX) is an established therapy in the treatment of psoriatic arthritis and rheumatoid arthritis. Zachariae et al., showed in a study with 59 psoriasis patients that continuous combination therapy with etanercept plus MTX for 24 weeks was superior to therapy with etanercept and a reduction in MTX therapy (in the first four weeks).[16] Etanercept plus methotrexate was more effective than etanercept monotherapy as measured by a significantly higher psoriasis area and severity index (PASI) 75 at week 24 (primary endpoint) and a significantly higher PASI 75 at week 12, PASI 50 at weeks 12 and 24, and PASI 90 at weeks 12 and 24.[17] The European League Against Rheumatism recommends the combination of a synthetic disease-modifying antirheumatic drug (DMARD) (such as methotrexate) plus a TNF blocker in patients with psoriatic arthritis with active arthritis and an inadequate DMARD response.[18]

Conclusion

This case report highlights that high index of suspicion of underlying HPA axis suppression should always arise in chronic psoriatic patients who have clinical features of Cushing syndrome. Planned withdrawal of steroid under the cover of short acting systemic steroid for short duration along with combination of immunosuppressants are required for excellent recovery in case of development of pustular erythroderma.

What is new?

There are very limited reports of self medication in the form of steroid or intake of corticosteroid mixed with homeopathic pills leading to complicated course of psoriasis. Work up for HPA axis suppression, planned withdrawal of steroid under the cover of short acting systemic steroid for short duration along with combination of systemic immunosuppressants is the key in the management of such cases.