INTRODUCTION

Atopic dermatitis (AD) is a chronic inflammatory skin condition usually seen in children but can also occur in adults. AD varies clinically with age. Infants and young children have scalp, face, and extensor involvement, whereas there is a predominant flexural association in older children and adults. Adults with AD may have a chronic, persistent, or relapsing-remitting course since childhood or may clinically present in adulthood. Adult-onset AD describes its manifestations in people aged more than 18 years. Unlike the infantile or childhood phase, the adult AD patients can present with lesions of varying morphology, thereby mimicking other diseases, which makes it a diagnostic challenge.

Tofacitinib is a janus kinase (JAK) inhibitor that acts mainly by inhibiting JAK-1 and 3 pathways. It is a novel drug and has been tried with beneficial effects in various inflammatory dermatoses. The advent of JAK-signal transducers and activator of transcription (STAT) inhibitors has opened another avenue for the treatment of AD. Various studies have established the role of baricitinib, upadacitinib, and abrocitinib in AD. However, the effectiveness of oral tofacitinib is yet to be established. Hence, this study aims to assess the potency of oral tofacitinib in adult-onset AD.

CASE SERIES

A total of 16 patients of age ≥18 years with moderate-to-severe AD who were clinically diagnosed as per Hanifin and Rajka criteria, and classified according to SCORing AD (SCORAD) and eczema area and severity index (EASI) score, were included. The disease had a chronic course of ≥6 months, and prior treatment with corticosteroids (topical and oral), anti-histamines, and other immunosuppressives (methotrexate and cyclosporine) for ≥3 months had a transient and minimal effect. The patients presented with lesions of varying morphology, including prurigo, seborrheic dermatitis-like lesions, palmoplantar eczema, lichenified lesions, and nummular eczema [Table 1]. Other differentials of seborrheic dermatitis and psoriasis were excluded based on history, cutaneous presentation, and non-specific biopsy findings. Patch testing was done to rule out air-borne or allergic contact dermatitis. Serum immunoglobulin E (IgE) levels were assessed at baseline.

The patients were planned for oral tofacitinib, for which a panel of tests, which included complete blood count (CBC),liver and renal function tests (liver function test [LFT] and renal function test [RFT]), fasting lipid profile, serological testing for hepatitis B, hepatitis C, human immunodeficiency virus, tuberculosis testing (Mantoux and Quantiferon TB gold tests), and pregnancy test were performed. Tofacitinib was started orally at a 5 mg twice-daily dose along with moisturizers after the reports came within normal limits.

The patients were followed up every month for 3 months while on treatment. Clinical response was assessed based on the improvement of EASI, SCORAD, dermatology life quality index (DLQI), and peak pruritus numerical rating scale (PP-NRS). The patients were also evaluated for any flares or adverse effects to the drug. CBC, LFT, and RFT were repeated after 1 month of treatment and then at the end of 3 months thereafter to look for any derangements. Tofacitinib was then tapered to once daily, then alternate days, twice weekly dosing for the next 3-6 months, and then stopped.

RESULTS

The study group included 7 males and 9 females. Their ages ranged from 23-58 years. The average duration of illness was 1.8 years, the shortest being 7 months and the longest being 4 years. 7 patients had raised serum IgE levels. At the initial visit, the mean EASI was 21.9 and the mean SCORAD was 49.7.

The patients were started on tofacitinib and followed up monthly to monitor disease activity. The mean EASI reduced to 5.5, and SCORAD to 17.7 (p <0.0001 in unpaired t-test). 10 patients showed >75% reduction in EASI score, and three patients showed around 50% reduction in EASI score. There was a reduction of ≥4 points in PP-NRS in all patients with notable alleviation of pruritus. All patients showed a significant improvement in the quality of life, with the mean DLQI reducing from 16 to 4.92 [Table 2 and Figures 1-3]. Tofacitinib was well-tolerated by 13 patients, with minimal side effects (gastrointestinal intolerance, mild derangement of lipid profile). Tofacitinib had to be discontinued in 3 patients. One patient developed neutropenia at 1 month of starting tofacitinib. Two patients had herpes zoster reactivation, which presented with vesicles and pustules over an erythematous background following a dermatomal distribution with severe pain. Two patients showed mild lipid profile derangement. They were advised to take a once-daily dose of tofacitinib along with a hyperlipidemic diet focusing on lower cholesterol and triglycerides, more soluble fiber, and increased unsaturated fat intake. Furthermore, one patient was advised oral atorvastatin.

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Figure 1:

Prurigo-like lesions over the bilateral dorsum of hands, arms, and trunk in a female patient with adult-onset atopic dermatitis. (a) At baseline, (b) After 3 months of oral tofacitinib.

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Figure 2:

Hyperkeratotic bilateral hand eczema in a male patient of adult-onset atopic dermatitis. (a) At baseline, (b) After 2 months of oral tofacitinib, (c) After 3 months of oral tofacitinib.

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Figure 3:

Photosensitive eczematous lesions over the face and neck in a female patient of adult-onset atopic dermatitis. (a) At baseline, (b) After 3 months of oral tofacitinib.

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DISCUSSION

AD is a chronic cutaneous condition characterized by intensely pruritic lesions. It is usually seen in early childhood and may progress to old age or may arise de novo in adults. The terminology “adult-onset AD,” coined by Bannister et al. in 2000, describes individuals manifesting with AD at a later age of ≥18 years.^[1] According to the global research on AD in adults, its prevalence ranges from 2% to 17.6%, with increased incidence in developed countries.^[2] Based on the serum IgE levels, AD can be classified as extrinsic (raised IgE) and intrinsic (normal levels of IgE). Extrinsic AD usually presents with flexural lichenification, whereas follicular and nummular lesions are predominant in intrinsic AD.^[3] Moreover, the environmental and physical factors that cause AD in adults differ from those in infants and children, thereby leading to the different patterns of involvement and morphologies in older age groups. Unlike flexural predilection in childhood, adults can present with nummular eczema, prurigo-like lesions, lichen simplex, psoriasiform, seborrheic dermatitis-like lesions, photodermatoses, airborne contact dermatitis-like plaques, palmoplantar eczemas, lichenoid, and erythrodermic lesions. It commonly involves the hands in females and the eyelids in males.^[4]

Hanifin and Rajka criteria or the UK Working Party’s diagnostic criteria have been instrumental in the diagnosis of AD in the pediatric population. However, its validity in diagnosing adult-onset AD still remains to be tested. A few features in the criteria are inconsistent with adult presentation and may hinder the diagnosis. Hence, adult-onset AD is essentially a diagnosis of exclusion. Conditions such as seborrheic dermatitis, psoriasis, allergic contact dermatitis, scabies, and lymphoma should be ruled out to reach the diagnosis.^[5-7]

Emollients and antihistamines are the mainstay of treatment in all forms of AD. Systemic corticosteroids, immunosuppressives, and biologics are considered in severe and refractory cases. Appropriate therapy should be chosen based on the severity of the condition, presence of comorbidities, and patient profile.

JAK-STAT pathway leads to activation of various inflammatory cytokines such as interleukins -4, 5, 13, and tumor necrosis factor-alpha, which are implicated in AD. JAK inhibitors block the pathway, thereby downregulating the expression of these cytokines. It has been tried in AD with promising results. Tofacitinib is a small molecule immunomodulator that acts by inhibition of the JAK-STAT pathway (JAK 1 and 3 inhibition). Moreover, it also modulates the barrier integrity and regulates the peripheral nerves, which cause pruritus.

Topical cream formulation of ruxolitinib has received approval for mild-to-moderate AD, whereas systemic JAK inhibitors such as abrocitinib and upadacitinib have been approved by the Food and Drug Administration (FDA) for moderate-to-severe AD. Baricitinib was approved in the European Union and Japan due to its impressive results. However, studies on the off-label use of tofacitinib in AD are scarce and have been mentioned in Table 3.^[8-12] Like the previous studies, our case series suggests that tofacitinib is a good steroid-sparing alternative in the therapeutic armamentarium of AD. However, it is not devoid of side effects and has yet to receive approval. The FDA has issued a boxed warning regarding increased incidences of thromboembolism, malignancies, major adverse cardiovascular events, and infections such as tuberculosis and hepatitis. Hence, regular follow-ups with detailed history-taking, clinical examination, and consistent monitoring of laboratory parameters are of paramount importance, especially when administered in the adult and elderly population.

CONCLUSION

Tofacitinib was safe, efficacious, and well-tolerated by most of the patients as observed in our study. The promising results with this molecule suggest that it can be considered as an upcoming cost-effective therapeutic option in severe AD. Further randomized controlled studies are required to validate the findings.