Tofacitinib in the treatment of recalcitrant cases of psoriasis vulgaris

INTRODUCTION

Psoriasis is a chronic papulosquamous disorder of multifactorial etiology. The disease has a relapsing and remitting course with no cure till date. There are many treatment modalities available including methotrexate, cyclosporine, acitretin, apremilast, and phototherapy. However, each of these are associated with side effects. Methotrexate is an inexpensive and popular immunosuppressant but has the risk of mucositis, pneumonitis, pancytopenia, and cutaneous ulceration due to acute toxicity with dose-dependent or idiosyncratic mechanisms.^[1,2] Cyclosporine can result in hypertension, renal toxicity and it is recommended to keep the duration of its use below 2 years.^[3] Acitretin can cause hyperlipidemia, hepatotoxicity, and its prolonged teratogenic potential limits its use in women of child bearing age group. Phototherapy facility is not available at all setups and patients may be unable to make multiple hospital visits each week for it.

Biologics are expensive and development of anti-drug antibodies can render even these expensive drugs ineffective. Hence, in patients who have exhausted these modalities, the treatment options are limited. We successfully treated five such cases with tofacitinib.

CASE REPORTS

Patient 1 was a 70-year-old male with chronic plaque psoriasis since 18 years. He was on methotrexate for more than 5 years with cumulative dose exceeding 3 grams. His liver function tests were deranged. Acoustic radiation force impulse imaging, used as a measure for liver fibrosis, was suggestive of severe liver scarring. The patient had received phototherapy for over 2 years with no improvement. The patient developed severe diarrhea with apremilast and cyclosporine had to be discontinued due to development of hypertension and rising creatinine values. Despite these treatments, his Psoriasis Area and Severity Index (PASI) was 19.5 with around 60% involvement of body surface area (BSA) [Figure 1a]. After performing the required baseline investigations, the patient was started on tablet tofacitinib 5 mg once a day after getting a clearance from gastroenterology. Within 2 months of treatment, PASI 75 was achieved with <10% BSA involvement [Figure 1b].

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Figure 1:

(a) Pre-tofacitinib photo of patient 1. (b) Post-tofacitinib photo of patient 1.

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Patient 2 was a 42-year-old male with psoriasis since 20 years with history of joint pain and swelling. He was treated with methotrexate on and off for 10 years with cumulative dose exceeding 4 g but was stopped due to deranging liver function and episodes of malena. Ultrasonography of abdomen showed hepatomegaly and altered liver echotexture and liver biopsy was suggestive of methotrexate induced liver injury. The patient also received cyclosporine on and off for a duration of 3 years but developed nephrotoxicity. A renal biopsy suggested focal segmental glomerulosclerosis, 20% interstitial fibrosis and tubal atrophy. He also developed a rarely reported side effect of cyclosporine – sensorineural hearing loss.^[4] The patient was unable to make multiple hospital visits for phototherapy and developed severe diarrhea with apremilast. At the time of presentation to our hospital, the patient had PASI of 26.2 and BSA involvement of more than 60%. He was found to be positive for hepatitis C virus (HCV) antibody, but HCV ribonucleic acid was undetectable. After performing the required investigative workup and obtaining clearance from gastroenterology, the patient was started on injection secukinumab. A total of five loading doses of 300 mg each were given at weekly intervals and the patient showed complete lesion clearance. Following this, he was started on monthly maintenance doses which, however due to limited supply, were discontinued. The patient flared within 3 months of stopping the injections and PASI increased to 14.2 and BSA involvement was 40%.

The patient was started on tofacitinib 5 mg twice a day and, within 1 month, PASI 75 was obtained. The BSA involvement reduced to <10% and PASI reduced to 3.3.

Patient 3 was a 41-year-old man with psoriasis vulgaris since 10 years. The patient showed no improvement with 15 mg weekly dose of methotrexate. He showed some improvement with cyclosporine which was given for 1 year but lesions flared as soon as the dose was tapered and the drug was stopped. The patient did not tolerate apremilast due to troublesome diarrhea. Phototherapy too showed no improvement. His lesions improved with injection secukinumab, but his maintenance therapy was interrupted due to the COVID-19 pandemic. At his subsequent visit to the hospital, his PASI was 32 and around 70% of BSA was involved [Figure 2a]. The patient was worked up and started on tablet tofacitinib 5 mg twice daily and, within 3 months, PASI 75 was achieved and BSA involved reduced to 15% [Figure 2b].

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Figure 2:

(a) Pre-tofacitinib photo of patient 3. (b) Post-tofacitinib photo of patient 3.

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Patient 4 was a 52-year-old man, a known case of chronic kidney disease with psoriasis vulgaris since 20 years. He was on methotrexate on and off for around 15 years with no improvement. Due to his renal condition, usage of cyclosporine was restricted. Apremilast did not show any significant improvement. The patient was worked up for tofacitinib and clearance was obtained to start it at 5 mg once daily dosing only. His baseline PASI score was 19.9. He was started on tofacitinib 5 mg once daily dose and, within 2 months, his lesions showed near complete clearance. His PASI reduced to 2.4 by 3 months.

Our 5^th patient was 43-year-old man with psoriasis since 15 years with episode of erythroderma and hospital admission 7 years back. He was treated with multiple courses of cyclosporine and flared each time it was tapered. Methotrexate was given for 3 years with no improvement. Apremilast too showed no improvement. Next, the patient was worked up and started on injection secukinumab. Although he showed significant improvement with secukinumab, the lesions flared within 1 month of stopping. At the time, the patient was being worked up for tofacitinib that his PASI was 22.9 with BSA involvement of about 70% [Figure 3a]. Within just 1 month of starting tofacitinib 5 mg twice daily, PASI reduced to a mere 2.1 and BSA involvement reduced to 5%. Thus, PASI 90 was achieved in just 1 month [Figure 3b].

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Figure 3:

(a) Pre-tofacitinib photo of patient 5. (b) Post-tofacitinib photo of patient 5.

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DISCUSSION

We present five cases of psoriasis who were refractory to various systemic therapies [Table 1]. In all patients, oral tofacitinib resulted in significant improvement with PASI 75 being achieved as early as 1 month (patient 2) and PASI 90 being achieved as early as 1 month (patient 5). All our patients are maintaining the results achieved with tofacitinib till date and no side effects have been noted.

Tofacitinib is a small molecule which inhibits Janus associated kinase 1 and 3. It is Food and Drug Administration (FDA) approved for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and juvenile idiopathic arthritis above 2 years of age.^[5] The off label uses in dermatology include alopecia areata, atopic dermatitis, psoriasis vulgaris, vitiligo, dermatomyositis, lichen planopilaris, pyoderma gangrenosum, and morphea.^[6]

Psoriatic skin shows upregulated Janus kinase (JAK)/signal transducers and activators of transcription signaling as compared to healthy skin, causing the production of multiple proinflammatory cytokines such as interferon-gamma, interleukin (IL)-12, and IL-23.

Inhibition of JAK signaling therefore has an overall anti-inflammatory effect, with decreased expression of proinflammatory cytokines.^[7-9]

Various adverse effects have been reported with tofacitinib use including infections, malignancies, deep vein thrombosis, and hyperlipidemia. As per FDA recommendations, before starting the drug one must check for latent tuberculosis especially in a country like India the tests which should be done before starting medications and periodically include complete blood count, lipid level and liver function tests.^[10]

CONCLUSION

Although previous studies have demonstrated the efficacy of tofacitinib in moderate to severe large plaque psoriasis, our case series shows its efficacy in difficult cases of psoriasis where patients are refractory to conventional modalities of treatment. Hence, we conclude that tofacitinib may be an effective therapy for the management of recalcitrant psoriasis.