ORAL CYCLOSPORINE VS TOFACITINIB IN MODERATE TO SEVERE ATOPIC DERMATITIS; A 1:1 PARALLEL, NON INFERIORITY, RANDOMIZED CONTROLLED CLINICAL TRIAL IN PAEDIATRIC POPULATION

Atopic dermatitis (AD) is a chronic relapsing highly pruritic skin condition. It usually starts in

early childhood but can occur at any age. AD affects 2%-5% of the general population, with

10%-20% in infants and children and 1%-3% in adults. [1]

Patients of AD usually have genetically determined risk factors affecting the skin barrier

function or the immune system. The interaction of a dysfunctional epidermal barrier and

environmental allergens leads to the development of the disease. [10]

There is a clinical difference in age of onset, morphology, severity, and distribution of skin

lesions. The patient may present with erythema, itchy papules /papulovesicles which may

become excoriated and lichenified & maybe associated with dryness or secondary infections in

individuals with a personal or family history of atopy. AD and food allergy have a predilection

for infants and young children while asthma and rhinoconjunctivitis predominate in older

children and adolescents. This characteristic age dependent progression of atopy is known as

atopic march. [9]

It is diagnosed mainly based on history, clinical examination & if the Hanifin Rajka criteria or

UK working Party criteria is fulfilled. Scoring systems such as SCORing Atopic Dermatitis

(SCORAD) & Eczema Area and Severity Index (EASI) are predominantly used to assess

disease severity.

EASI score of 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates

mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and

greater than 51 indicates very severe disease. [8]

The European Taskforce on Atopic Dermatitis defined severe atopic dermatitis as having an

eczema severity score (SCORAD) greater than 50 or “persistent” disease. [14] Around 2% of

patients have severe disease that does not respond adequately to conventional therapy. [4]

The treatment aims to reduce the symptoms, improve quality of life, decrease the degree and

frequency of flares, and reduce atopic comorbidities.

The mainstay of treatment in childhood remains emollients and topical corticosteroids, with

topical calcineurin inhibitors and phototherapy [3] being commonly used alternatives.

Cyclosporin A (CSA) is a systemic calcineurin inhibitor immunosuppressant agent widely used

for the treatment of severe atopic dermatitis (AD) unresponsive to conventional topical therapy

both in adults and children. It decreases production of IL-2 & other inflammatory cytokines &

prevents activation & proliferation of T cells. It is fast acting, allowing prompt induction of

remission. [5]

Tofacitinib exerts its mechanism of action by inhibiting intracellular cytoplasmic nonreceptor

tyrosine kinase JAK enzymes, which are involved in adaptive and innate immune reactions in

the process of immune-mediated inflammatory diseases (IMIDs).

The intracellular Janus kinases' natural role is to phosphorylate the signal transducers and

activators of transcription (STATs) enzymes which further influence gene expression and

impact hematopoiesis and immune cell function. The JAK-STAT signaling pathway plays a

major role in the pathogenesis of autoimmune diseases, such as RA. Similar to other JAK

inhibitors, tofacitinib blocks the phosphorylation and intracellular activation of signal

transducers and activators of transcription, further diminishing their inflammatory effects[7]

Levy et al have used tofacitinib in moderate to severe Atopic dermatitis and noticed a 66.6%

reduction in SCORAD [15]

Despite extensive studies regarding the treatment options for AD, no RCT has been yet

published that compares the safety and efficacy of these two drugs among Indian patients with

moderate to severe paediatric AD. Hence with the increase in prevalence & severity of AD in

paediatric population, this study will help to establish whether tofacitinib is not inferior to

cyclosporine in treatment of moderate to severe Atopic dermatitis

The patients meeting all the inclusion criteria & not meeting any exclusion criteria shall

be considered to participate in the study.

ï‚· A detailed history including the duration of the disease, associated medical conditions,

personal history and family history is to be taken.

ï‚· The patients are randomised according to random number generator and allocated to

two interventional groups.

ï‚· medication dosages for the two interventional groups:

CYCLOSPORINE 3 TO 5 MG/KG DAILY

TOFACITINIB 10-20 kg 3.2 ml oral solution twice daily

20-40kg 4 ml oral solution twice daily

40kg 5 ml oral solution twice daily

Both groups will be advised not to take any other systemic treatment or exposed to

phototherapy during the treatment and follow-up period. Only sedating antihistamines

and topical emollients will be allowed as adjuvant therapy.

ï‚· Assessment is done at baseline then 4 weeks ,8 weeks and 12 weeks

ï‚· For follow up:

ï‚· assessment schedule and outcome measures:

ï‚· To assess the outcome, clinical examination, SCORing Atopic Dermatitis (SCORAD),

Eczema Area and Severity Index (EASI) Investigator Global Assesment Score (IGA)

ITCH Visual Analogue Scale (ITCH VAS) and on follow up DFI (dermatitis Family

Impact Score) will be calculated

baseline investigations will be sent

CBC LFT RFT FASTING LIPID PROFILE SERUM ELECTROLYTES TB QUANTIFERON GOLD

BLOOD PRESSURE WEIGHT AND CHEST X RAY WILL BE DONE

then at 4 weeks 8 weeks and 12 weeks

CBC LFT RFT SERUM ELECTROLYTES FASTING LIPID PROFILE

will be repeated

Images will be taken at the start of

therapy and at each follow-up visit to

monitor changes in skin condition and

to assess improvement over time.

Any patient experiencing significant

side effects or adverse reactions to the

treatment will be promptly evaluated

and, if necessary, withdrawn from the

study.

withdrawl criteria

1. Remission doesn’t occur in 8 weeks SCORAD

doesn’t fall by 25%

2. Diagnosis of tuberculosis

3. Any active infection which warrants

hospitalization and stoppage of cyclosporine and

tofacitinib for 2 days

4. Dose dependent hematological decrease in CBC:

5. Lymphocyte count less than 500 cells/mm3 or in patients

who develop an absolute lymphocytic count less than 500

cells/mm3.

6. Neutropenia less than 2000 cells/mm3

7. Hb level drop more than 2gm/dl

8. Confirmed increase in liver enzymes more than3 X ULN

9. Increase in Sr creatinine more than 50% of baseline.

10. Increase in Total cholesterol level > 200mg/dl

11. Active cancer

12. Hyperkalemia >5.5 meq/dl

13. Persistent increase in age-appropriate BP reading

above the baseline BP of patient on two occasions

at least a day apart.

rescue criteria

appropriate medication will be used if side effects

are seen.

• If there is *flare with increase in IGA SCORE of

4 or higher , then systemic steroids shall be used

for 7 days.