Chemotherapy-Induced Systemic Sclerosis-Like Changes

Dear Editor, Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of skin and internal organs secondary to vasculopathy, inflammation, and fibrosis. In addition, various drugs like bleomycin, L-tryptophan, carbidopa, penicillamine, sodium valproate, cocaine, diltiazem, and taxanes can also induce SSc-like changes.[1] We encountered one such case of a 29-year-old diagnosed case of ovarian mucinous cystadenocarcinoma stage III, post-surgical excision, maintained on six cycles of chemotherapy containing carboplatin (200 mg) and paclitaxel (120 mg). She presented with a nine-month duration of progressive skin tightening of the distal upper and lower extremities and salt and pepper pigmentation (SPP) with onset after five months of starting chemotherapy. She complained of erythema and edema in the distal extremities prior to the onset of skin tightening; however, the patient denied a history of prior biphasic or triphasic Raynaud's phenomenon (RP). Cutaneous examination revealed skin thickening distal to elbows and knees (Modified Rodnan Skin Score 18) as well as generalized SPP [Figure 1]. In addition, whitish hard nodules suggestive of calcinosis cutis were present on both pinnae [Figure 1a]. Tendon friction rub was demonstrable over the tendons of the fingers. Dermoscopic examination of the nail fold of the left fourth finger showed nail fold changes (NFCs) – avascular areas, capillary dropouts, and hemorrhages consistent with SSc [Figure 2]. The rest of the mucocutaneous and systemic examination was unremarkable. Laboratory abnormalities include antinuclear antibody (ANA) 4+ with speckled and nucleolar patterns, and negative SSc-specific and non-specific antibodies (scl-70, anti-centromere, anti-RNA polymerase III, anti-SSA/SSB, anti-Sm, and anti-RNP). Histopathological examination from the forearm showed epidermal thinning with diffuse dermal collagenization. There were no changes in the pulmonary function test or high-resolution computed tomography of the chest. Radiological and laboratory work-up failed to reveal any residual malignancy. Oral nifedipine 10 mg daily, methotrexate 15 mg/week, and oral risedronate 5 mg/week were initiated without any further worsening of symptoms at 6 months follow-up. At one year follow-up (5 months after stopping chemotherapy), she reported improvement of skin lesions without recurrence of malignancy. Based on clinical features, positive ANA, and negative specific autoantibodies, and temporal correlation, a diagnosis of paclitaxel-induced SSc-like changes was considered.Figure 1: (a). Clinical image of the face showing salt and pepper pigmentation on a background of hyperpigmentation and binding down of skin. In addition, calcinosis cutis can be noted on the right ear (black circles). (b). Clinical image of the forearms and hands showing salt and pepper pigmentation with binding down of skinFigure 2: Dermoscopic examination of the nail fold of the non-dominant middle finger showing dilated loops, capillary dropouts, avascular areas, and hemorrhages (DermLite DL4 10x)Paclitaxel is an antimitotic agent that suppresses microtubule depolymerization, causing cell arrest at the G2/M phase. Reported cutaneous adverse effects of taxanes include alopecia, mucositis, hand-foot syndrome, cutaneous rashes, and, rarely, scleroderma-like changes.[2] The exact pathogenesis of SSc-like changes is unknown, but modulation of immune response and cytokine (tumor necrosis factor-α, interleukin-2, interleukin-6, and interferon) profile plays a role by stimulating fibroblasts.[3] The average latency to SSc after taxanes is one year, with prominent symptoms, including cutaneous edema, rapidly progressive skin thickening, early involvement of the lower extremities, and less facial involvement.[2] RP, digital pitting scars, or digital ulcers, and NFCs at disease onset are rare.[1,3-6] Capillary dropouts and gastroesophageal reflux disease (GERD) without Raynaud's and calcinosis cutis have been reported in taxane-induced SSc.[7] One-fourth of cases have positive ANA, but SSc-specific antibodies are negative.[2] Discontinuation of taxanes, corticosteroids, and/or other adjuvants constitutes the management.[2,7] Paraneoplastic SSc was not considered in our case, as a temporal association of clinical features was better with chemotherapy than with malignancy. Furthermore, paraneoplastic dermatoses tend to follow a parallel course with associated malignancies. In our patient, no residual malignancy was present at presentation of SSc. Other differentials of sclerodermoid disorders, like myxedema, graft-versus-host disease, and eosinophilic fasciitis, were ruled out in the absence of supporting clinical and investigational findings. Although GERD and NFCs were favoring idiopathic SSc, temporal correlation with paclitaxel, rapid progression of sclerosis and dyspigmentation, absence of digital pitted scars, other internal organ involvement, and negative SSc-specific antibodies favored the diagnosis of taxane-induced SSc. This case highlights that full-fledged SSc-like changes with NFCs, GERD, and positive ANA can be seen in drug-induced SSc. To the best of our knowledge, extensive SPP, calcinosis cutis, and tendon friction rubs have not been reported to date in drug-induced SSc. A high index of suspicion of drug as etiology is required to make a diagnosis of drug-induced SSc, especially in early stages, where symptoms may not develop fully. 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) We have not used artificial intelligence in preparation of this manuscript.