Pirfenidone-Induced Lichen Planus Pigmentosus in a Patient with Idiopathic Pulmonary Fibrosis

Dear editor, Pirfenidone is an antifibrotic and anti-inflammatory agent with a varied action spectrum, with the common result of decreased level of transforming growth factor-β (TGF-β), reducing fibroblast proliferation and myofibroblast differentiation, thus inhibiting collagen production and fibrosis.[1] Here, we report a patient with idiopathic pulmonary fibrosis (IPF) who developed lichen planus pigmentosus (LPP) after initiation of pirfenidone for treatment of IPF. A 53-year-old male patient of IPF on treatment with pirfenidone (600 mg twice daily) for 15 days, consulted for rapid evolution of multiple asymptomatic hyperpigmented skin lesions all over the body. There was no preceding pruritus or erythema. He was not on any other medication and had no history of using cosmetics. On examination, there were multiple, ill-defined brown-grey macules distributed symmetrically on the sides of the neck, upper limbs, chest, abdomen, and back [Figure 1a-c], sparing face and lower limbs. There was no erythema or scaling on the lesions. Mucosae and the nails were normal. A possibility of the pirfenidone-induced LPP was considered.Figure 1: Multiple, ill-defined dark-brown macules on (a) neck, (b) chest, (c) backDermoscopy (Dermlite DL4 dermoscope 10× magnification, polarized microscopy) showed reticular pattern of black-brown dots and globules, target sign, peri-eccrine globules, and irregular dots with peppering [Figure 2]. Histopathology showed basal cell damage and vacuolar changes, flattened rete ridges, significant pigment incontinence, and moderately dense perivascular and periadnexal lympho-histiocytic infiltrate, compatible with a clinical diagnosis of LPP [Figure 3a-c]. Pirfenidone was stopped, and the patient was shifted to nintedanib 150 mg per day. Topical mometasone furoate 0.1% cream was advised for 4 weeks for skin lesions. The development of new lesions ceased within 1 week of discontinuing pirfenidone. After 1 month of follow-up, there was minimal improvement in the size and pigmentation of the existing lesions.Figure 2: Dermoscopy showing reticular pattern of black-brown dots and globules (black large circle), irregular peppering of dots (black rectangular box), nonspecific granules/irregular dots (purple rectangular box), the target/owl sign (red small circle) and peri-eccrine globules (black small circle) (Dermlite DL4,10×)Figure 3: (a) Biopsy showing flattened rete ridges, multifocal basal cell damage, along with vacuolar basal cell changes, focal follicular plugging, marked pigment incontinence, moderately dense inflammatory infiltrate composed of lympho-histiocytes (H and E, 100×); (b, c) Basal layer damage with vacuolar changes, significant pigment incontinence admixed with perivascular lympho-histiocytic infiltrate in papillary dermis (H and E; 400×)Pirfenidone is known to cause photosensitivity (12%) and skin rashes (30%).[2] Two initial reports of lichenoid drug rash (LDR), one of which was photo-distributed, have recently evoked the interest of dermatologists in this drug.[3,4] In a single-center report from Turkey, among the 13 patients with pirfenidone-induced cutaneous adverse drug reactions (CADR), six had clinical and histopathological features of lichenoid reaction.[5] Recently, there is a report of pirfenidone-induced LPP,[6] similar to the this case. The pathogenesis of LDR due to pirfenidone is yet to be explored. It decreases the levels of transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α), the proinflammatory cytokines involved in keratinocyte apoptosis in lichen planus (LP).[7] There is increased expression of TNF-α in lesional skin of LP.[7] Though the pathogenesis of LP is multifactorial, hypothetically, the drug should have had some ameliorative effect on LP rather than inducing LDR. According to the findings of phase III trials, most of the CADRs due to pirfenidone occur early in therapy,[2], as in the index patient. The skin lesions are easily manageable, reversible, and decreases gradually after the initial 6 months of therapy, with variable intensity on further continuation of treatment.[2] The management protocol proposed in the consensus from these trials encompasses the use of protective clothing, sunscreens, dose reduction, and either topical or systemic steroid therapy. If there is no response, it is recommended to temporarily withhold the drug and subsequently consider a slow escalation.[2] In these trials, dose reduction and stoppage of therapy for skin-related adverse events were required for 46% and 41% patients, respectively.[2] IPF is a severe disease associated with great morbidity, a downhill course, and limited therapeutic options.[2] Pirfenidone-associated CADRs do not warrant abrupt stoppage of the drug, as was inadvertently performed in this case, but require judicious dose monitoring, patient-education, and close follow-up. Gold therapy, amla oil, hair dye, and mustard oil containing allyl isothiocyanate are considered etiologic or triggering factors.[8] Recently, tamoxifen, a selective oestrogen receptor modulator, and methadone, an oral opioid used for pain management, have been identified to induce LPP.[8] LPP may also be a presenting feature of pirfenidone-associated CADR. The pathogenesis of pirfenidone-induced LDR needs to be explored because of its inhibitory effect on the cytokine-milieu of LP. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his 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.