De novo Generalized Pustular Psoriasis: A Tofacitinib-Induced Paradoxical Adverse Event

Dear Editor, Tofacitinib is an oral small-molecule Janus kinase (JAK) inhibitor and is Food and Drug Administration (FDA)-approved for the treatment of moderate to severe rheumatoid arthritis (RA), ulcerative colitis, psoriatic arthritis, and polyarticular juvenile idiopathic arthritis. Pustular psoriasis is a distinct subset of psoriasis having multiple triggers, among which drugs like nonsteroidal anti-inflammatory drugs, beta-blockers, lithium, terbinafine, withdrawal of corticosteroids, cyclosporine, and Ustekinumab are implicated. Tumor necrosis factor-alpha (TNF-α) inhibitors are known to trigger paradoxical pustular psoriasis. Paradoxical psoriasis or psoriasiform lesion is an adverse effect, represented by the occurrence of a psoriasiform lesion or exacerbation of psoriasis caused by the drugs used for the management of psoriasis.[1] There are only a few case reports about tofacitinib inducing psoriasiform lesions and palmoplantar pustulosis.[1,2] Here, we present a case of de novo generalized pustular psoriasis (GPP) after the use of tofacitinib in a patient with RA. A 51-year-old female, known case of hypothyroidism and seropositive RA, presented with a sudden onset of multiple tiny pus-filled lesions over a red background associated with a burning sensation behind both knee joints. It gradually progressed to involve other areas of the body over a span of 2 months. She had no personal or family history of psoriasis or psoriatic arthritis. She had taken methotrexate, leflunomide, hydroxychloroquine, and glucocorticoids at different times for RA with limited response. For the last 7 months, she has been on tofacitinib 5 mg once a day for RA, along with isoniazid 300 mg once a day for tuberculosis chemoprophylaxis prescribed by her rheumatologist, as her QuantiFERON-TB Gold test was positive. Dermatological examination revealed multiple well-defined pustules of size 1–2 mm over an erythematous background present on the neck, retroauricular area, trunk, bilateral upper and lower extremities, and both groins [Figure 1a]. At a few places, dried pustules formed a collarette of scales. A punch biopsy was taken, and histopathological examination (HPE) revealed minimal hyperkeratosis with a subcorneal pustule, focal spongiosis, with perivascular mixed inflammatory cell infiltration at superficial dermis, which was suggestive of pustular dermatoses. Based on history, clinical examination, and HPE, a diagnosis of acute generalized exanthematous pustulosis (AGEP) secondary to tofacitinib or isoniazid was made. After stopping all drugs, she was started on cyclosporine 100 mg twice a day, and the lesions completely resolved within one and a half months.Figure 1: (a) Multiple well-defined pustules on an erythematous background present on the neck, chest, abdomen, and both upper extremities on presentation. (b) Similar lesions on restarting tofacitinib. (c) After 1 month of discontinuing tofacitinib and treatment with cyclosporineHowever, because of the exacerbation of RA symptoms, she was again started on only tofacitinib 5 mg once daily by her rheumatologist. After 15 days, she again developed similar lesions all over the body [Figure 1b]. For this, she again visited our outpatient department, and a differential diagnosis of AGEP, GPP, and inflammatory tinea was made. Potassium hydroxide mount of skin scrapings showed no fungal elements. Gram stain from the pustule revealed a few pus cells and no organisms. HPE revealed neutrophilic collections in the upper epidermis, parakeratoses, a diminished granular cell layer, and elongation of rete ridges [Figure 2]. Dermis had dilated capillaries and a superficial perivascular inflammatory infiltrate composed of lymphocytes and neutrophils. All these findings were suggestive of pustular psoriasis. All the drugs were discontinued, and she was again started on cyclosporine 100 mg twice a day, after which lesions resolved completely within 1 month [Figure 1c].Figure 2: (a) Epidermis shows hyperkeratosis, parakeratosis, and a diminished granular cell layer with elongation of rete ridges. Dermis has dilated capillaries and a superficial perivascular inflammatory infiltrate composed of lymphocytes and neutrophils (Hematoxylin and eosin, 40×). (b) Higher magnification shows neutrophilic collections (spongiform pustule of Kogoj) in the upper epidermis (Hematoxylin and eosin, 100×)Tofacitinib, although effective, according to many case reports, can paradoxically induce various dermatological conditions like psoriasiform lesions, subacute cutaneous lupus erythematosus, and palmoplantar pustulosis.[1-3] On an extensive survey of the literature, no documented case of tofacitinib-induced de novo GPP was found. GPP has been reported in RA patients on leflunomide, hydroxychloroquine, and TNF-α inhibitors like etanercept, infliximab, adalimumab, and golimumab.[4,5] FDA-approved drugs like methotrexate, sulfasalazine, cyclosporine, and azathioprine; and biologics like abatacept, rituximab, tocilizumab, and sarilumab, can be used in RA patients vulnerable to drug-induced GPP. The clinical course in our case suggested that tofacitinib caused GPP, as the lesions subsided after stopping tofacitinib, then reappeared after restarting it. The mechanisms by which tofacitinib caused this paradoxical psoriasis remain unknown. Tofacitinib inhibits TNF-α effects by blocking the JAK/STAT pathway, thereby increasing interferon (IFN)-α secretion from plasmacytoid dendritic cells, which then plays a key role in the early induction of psoriatic skin lesions.[6,7] According to Erol et al.,[1] tofacitinib inhibits JAKs and causes the downstream activation of multiple cytokines, including IFN-α. Imbalance of IFN-α and IFN-γ may plays a role in the pathogenesis of tofacitinib-induced psoriasiform lesions. Another possible pathogenic mechanism is the expansion of pathogenic Th1 and Th17 cells in the peripheral lymph nodes, which occurs due to the decreased presence of these cells in the inflamed synovium in RA.[1] Authors’ contributions We confirm that all authors have read and approved the manuscript for submission. All authors meet authorship criteria, and the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.