Abstract

Objective

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic, and fatal lung disease associated with the inevitable loss of lung function. Pirfenidone, which has antifibrotic properties and has been used orally in recent years, slows down the progression of the disease and increases survival rates. However, photosensitive skin rash caused by absorbing ultraviolet rays is the most frequently encountered adverse effect in clinical practice.

Methods

Thirteen patients who were treated for IPF in the department of chest diseases between September 2018 and January 2022, used pirfenidone, and applied to the dermatology outpatient clinic due to rash were retrospectively examined. During this period, the number of patients receiving pirfenidone for IPF in chest diseases was fifty-six.

Results

In dermatological examination, scaly plaques on an erythematous background were common in seven patients, whereas lichenoid papules and plaques were dominant in six. In the histopathological evaluation of biopsies taken from the lesional skin area, the findings were consistent with superficial perivascular dermatitis in two, psoriasiform dermatitis in five, and lichenoid reaction pattern in six patients. When photosensitivity reactions occurred, pirfenidone treatment was continued in eleven patients at a reduced dose, and only two patients discontinued pirfenidone and switched to nintedanib therapy.

Conclusion

We aimed to show that photosensitivity reactions can be managed in the majority of patients without discontinuing pirfenidone, which plays a vital role in the treatment of IPF symptom control and survival by reducing the dose, using sun protection, and taking additional protective measures, and to provide further insight to clinicians in this regard.

Keywords:

Pirfenidone, idiopathic pulmonary fibrosis, photosensitivity, drug eruption

INTRODUCTION

Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia of unknown cause characterized by chronic, progressive fibrosis. The walls of the alveoli in the lungs thicken with scarring in this disease, which is observed mainly in older adults. It causes long-term cough, shortness of breath, fatigue, weakness, loss of appetite, and weight loss, and has a serious course (1). It also causes progressive and permanent damage to the lungs. Oxygen transfer from the lungs thickened by scar tissue to the blood circulation system is reduced, negatively affecting all organs. If left untreated, severe hypoxemic cases develop pulmonary hypertension and right heart failure. The average survival time of patients diagnosed with IPF is 2-5 years (2). The timely diagnosis of IPF is crucial but, unfortunately, is often delayed. Treatment of this disease that causes irreversible damage aims to reduce the patient’s symptoms and slow the progression of the disease. In recent years, two antifibrotic agents that can slow the progression of IPF have taken their place among the treatment options. Pirfenidone and nintedanib were shown to partially prolong life expectancy and improve quality of life by preventing the progression of fibrosis in the lung when started at an early stage (3). Pirfenidone transforming growth factor-beta has an antifibrotic, anti-inflammatory effect by inhibiting the overexpression of fibroblast growth factor, proliferation and transformation of fibroblasts into myofibroblasts, and collagen synthesis (4, 5). This increasingly used agent’s most common side effects are related to the skin and gastrointestinal system. The other antifibrotic agent, nintedanib, most commonly causes diarrhea. Cutaneous drug reactions, which are frequently encountered in dermatology practice, can occur in various severities, ranging from asymptomatic to severe clinical manifestations. Although pirfenidone, one of the antifibrotic drugs that has found increasing use in recent years, is well tolerated, it can cause widespread phototoxic and photoallergic reactions on the skin (6). It may be necessary to reduce the dose or change the current treatment, considering the clinical course, lesion severity, and patient tolerance. In the literature, data on skin rash caused by pirfenidone are limited to case reports, and there are few publications with extensive studies on the prognosis. In this article, we aimed to review the skin rash caused by pirfenidone, its clinical course, and its treatment and to provide further insight to clinicians in this regard.

METHODS

Thirteen patients who were treated by the chest diseases department at Necmettin Erbakan University Faculty of Medicine Hospital for IPF between September 2018 and January 2022, used pirfenidone, and applied to the dermatology outpatient clinic due to rash were retrospectively examined. During this period, the number of patients receiving pirfenidone for IPF in chest diseases was 56. The patients’ age, gender, clinical findings, time of starting and stopping pirfenidone treatment, lesional skin histopathology findings, skin-specific treatment, and responses were obtained from file records. Forty-four (79%) of 56 patients were male and 12 (21%) were female. Eleven (85%) of the cases with drug reactions were male.

Ethical approval for the study was obtained from the Pharmaceutical and Non-Medical Device Research Ethics Committee of Necmettin Erbakan University Meram Faculty of Medicine (decision number: 2020/2429, date: 17.04.2020). Patients with any photosensitive skin disease or a history of photosensitizing drug or non-photosensitizing drug use were not included in the study. The patients did not have any history of chronic inflammatory skin diseases, such as psoriasis and lichen. Informed consent was obtained from all patients participating in the study.

Statistical Analysis

The data were examined using SPSS 22.0 statistical software.

RESULTS

IPF between September 2018 and January 2022 who used pirfenidone and applied to the dermatology outpatient clinic due to rash were retrospectively examined. During this period, the number of patients receiving pirfenidone for IPF in chest diseases was 56. Forty-four (79%) of the 56 patients were male and 12 (21%) were female. Of the 13 patients included in our study, 11 were male (85%), and two were female. Their average age was 78.61 years (range 69-83). The average time from the onset of skin symptoms on pirfenidone for IPF was 5 months (mean: 5.15, minimum: 3, maximum: 12).

The most common site of lesions caused by pirfenidone was the hand in eleven of the patients. Seven patients had lesions on the feet, four on the neck, three on the face, and three on the arms. One patient also had photosensitivity lesions on the trunk, one patient with the lip, and two on the anterior front of the tibia. In dermatological examination, scaly plaques on an erythematous background were common in seven, while lichenoid papules and plaques were dominant in six of our patients (Figure 1,2).

In the histopathological evaluation of biopsies taken from the lesional skin area, the findings were consistent with superficial perivascular dermatitis in two, psoriasiform dermatitis in five, and lichenoid reaction pattern in six patients (Figure 3,4). All histopathologies showed necrotic keratinocytes and eosinophil infiltration, consistent with drug eruption. When photosensitivity reactions occurred, pirfenidone treatment was maintained in 11 patients by decreasing the dose, and two patients stopped using pirfenidone and were switched to nintedanib therapy. The two patients who were switched to nintedanib treatment were patients with resistant drug reactions that did not respond to treatments. All patients were treated with topical corticosteroids and antihistamines, and full recovery was observed in six patients within an average of 3.3 weeks (range 2-4), with no recurrence observed. In five patients, a 70-80% recovery was observed in an average of 6.4 weeks (range 4-8), and recurrence was observed within 1 year. In two patients, there was a 60-70% improvement in an average of 9 weeks (between 8-10) and occasional relapses were observed during the 1-year period. Relapse occurred in patients who continued pirfenidone but were controlled with topical corticosteroid and antihistamine treatment. The clinical characteristics of all patients are summarized in Table 1.

DISCUSSION

The common side effect of pirfenidone is photosensitive rashes, particularly in sun-exposed areas such as the face, neck, hands, and arms. Apart from pirfenidone, low-molecular-weight diuretics, nonsteroidal anti-inflammatory drugs, and antibiotics such as tetracycline-fluoroquinolones-sulfonamide are other essential drugs that can cause photosensitivity (7). Photosensitive drug reactions are divided into two major types: phototoxic and photoallergic. In phototoxic drug reactions, ultraviolet light interacts with the drug or its metabolites on the skin and causes nonimmunological cellular damage with the reactive oxygen molecules formed (8). In photoallergic reactions, ultraviolet rays convert drugs into immunologically active metabolites that stimulate cell-mediated hypersensitivity, causing rash (9). Since all photoallergic chemicals bind to proteins with the formation of free oxygen radicals, there are publications stating that the first step of photoallergic reactions is phototoxicity (10, 11). In clinical distinction, early-onset reactions can be evaluated as phototoxic and late-onset reactions as photoallergic. They are very difficult to distinguish clinically and can often be seen together (11). Photoallergic reactions have a more chronic course than phototoxic reactions. In phototoxic reactions, lesions are generally limited to areas exposed to the sun, whereas in photoallergic reactions start primarily in areas exposed to the sun and spread to other regions over time (12).

Rashes were more common in male patients in our study. We attribute this result to the fact that IPF is more common in men. There is a male predominance in studies on the incidence and prevalence of IPF (13). In the literature, the average time between the initiation of pirfenidone and the appearance of skin findings was found to be four months, and in our study, this period was 5 months on average (6).

In our two patients whose rashes started in the 3^rd month of pirfenidone treatment, skin biopsy histopathological evaluation was consistent with superficial perivascular dermatitis. The pirfenidone dose was reduced, and the lesions responded to treatment with no recurrence. This suggests that the reactions were rather phototoxic. Although the lesions started later in most patients with histopathology indicating psoriasiform dermatitis or lichenoid dermatitis, a response rate of 60-80% was obtained from the treatment of rashes while continuing the low-dose pirfenidone, which is more suggestive of a photoallergic reaction. However, we also have two patients with early-onset rash of this character and a complete response to treatment. Therefore, it is almost impossible to make a precise distinction. Phototoxicity is the basis of all reactions observed.

In our study, rashes that occurred due to pirfenidone entirely or largely regressed in all patients after the dose was reduced without the need for discontinuation of the drug. Sun protection methods effectively prevent photosensitivity reactions due to pirfenidone and constitute an essential treatment step. Broad-spectrum sunscreens that provide protection against ultraviolet A and ultraviolet B should be used; exposure should be avoided during hours when the sun’s rays are most intense; heavy artificial light sources should be avoided; and protective clothing should be worn as much as possible (14). It is also important to avoid exposure to sunlight for a few hours following pirfenidone intake because of its high blood concentration to prevent the development of reactions (14). The dose should first be reduced in cases of photosensitive reactions, and mild reactions can be controlled by sun protection methods and symptomatic treatment of lesions. Once the symptoms subside and the lesion regress, the dose can be increased slowly. In extremely severe cases that cannot be controlled with simple symptomatic treatment, systemic corticosteroid treatment may be used, and pirfenidone may need to be discontinued.

CONCLUSION

In conclusion, it should be kept in mind that the most common adverse effect of pirfenidone is photosensitive skin rash. The rash can be asymptomatic, self-limiting, and in the form of mild lesions, or it can be chronic, covering large areas and causing severe symptoms that reduce quality of life. The effective treatment of IPF is limited, and photosensitivity drug rash can be controlled without discontinuing pirfenidone, which is important in this regard, by reducing the dose, taking adequate sun protection, and other additional measures (6). Informing the patient in this respect, patient compliance, and the clinician’s approach in this situation in light of this information are of great importance.

Footnote

Ethics Committee Approval: Ethical approval for the study was obtained from the Pharmaceutical and Non-Medical Device Research Ethics Committee of Necmettin Erbakan University Meram Faculty of Medicine (decision number: 2020/2429, date: 17.04.2020).

Informed Consent: Informed consent was obtained from all patients participating in the study.

Authorship Contributions

Surgical and Medical Practices: S.A.T., S.Y., A.A., A.Z., N.K., P.O., Concept: S.A.T., S.Y., A.Z., Design: S.A.T., S.Y., A.A., A.Z., Data Collection or Processing: S.A.T., S.Y., A.Z., N.K., P.O., Analysis or Interpretation: S.A.T., S.Y., A.A., A.Z., P.O., Literature Search: S.A.T., S.Y., Writing: S.A.T., S.Y.

Conflict of Interest: No conflicts of interest were declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

References

Satti LR, Yennapu NR, Inturi R, Surada R. A Rare Occurrence of Enchondroma in the Head of Femur in an Adult Male: A Case Report. J Orthop Case Rep. 2023;13:62-5.

Burgener FA, Kormano M. Differential diagnosis in conventional radiology. Thieme Publishing Group; 1985.

Nakamura T, Matsumine A, Asanuma K, Matsubara T, Sudo A. Treatment of the benign bone tumors including femoral neck lesion using compression hip screw and synthetic bone graft. SICOT J. 2015;1:15.

Rajasekaran RB, Jayaramaraju D, Palanisami DR, Agraharam D, Thippeswamy PB, Rajasekaran S. Role of impaction bone grafting of allografts in the management of benign lesions of the proximal femur. J Orthop. 2022;34:189-95.

Puri A, Agarwal M. Treatment of giant cell tumor of bone: Current concepts. Indian J Orthop. 2007;41:101-8.

Shih HN, Cheng CY, Chen YJ, Huang TJ, Hsu RW. Treatment of the femoral neck amd trochanteric benign lesions. Clin Orthop Relat Res. 1996:220-6.

Hu YC, Lun DX, Zhao SK. Combined anterior and lateral approaches for bone tumors of the femoral neck and head. Orthopedics. 2012;35:628-34.

Wijsbek AE, Vazquez-Garcia BL, Grimer RJ, Carter SR, Abudu AA, Tillman RM, et al. Giant cell tumour of the proximal femur: Is joint-sparing management ever successful? Bone Joint J. 2014;96:127-31.

Sharfman ZT, Atzmon R, Gortzak Y, Rotem G, Drexler M, Haviv B, et al. Hip arthroscopy for intra-capsular benign tumors: a case series. J Hip Preserv Surg. 2016;3:312-7.

Erol B, Topkar MO, Aydemir AN, Okay E, Caliskan E, Sofulu O. A treatment strategy for proximal femoral benign bone lesions in children and recommended surgical procedures: retrospective analysis of 62 patients. Arch Orthop Trauma Surg. 2016;136:1051-61.

George B, Abudu A, Grimer RJ, Carter SR, Tillman RM. The treatment of benign lesions of the proximal femur with non-vascularised autologous fibular strut grafts. J Bone Joint Surg Br. 2008;90:648-51.

Panchwagh Y, Joshi SK, Sancheti PK. Benign Aggressive Lesions of Femoral Head and Neck: Is Salvage Possible? Indian J Orthop. 2018;52:51-7.

Kundu ZS, Gogna P, Sangwan SS, Garg R, Kamboj P, Singla R. Benign lytic lesions of the femoral neck: mid-term results of extended curettage and sartorius muscle pedicle bone grafting. Arch Orthop Trauma Surg. 2013;133:457-62.

Singh P, Kejariwal U, Chugh A. A Rare Occurrence of Enchondroma in Neck of Femur in an Adult Female: A Case Report. J Clin Diagn Res. 2015;9:RD01-3.

Tepelenis K, Papathanakos G, Kitsouli A, Troupis T, Barbouti A, Vlachos K, et al. Osteochondromas: An Updated Review of Epidemiology, Pathogenesis, Clinical Presentation, Radiological Features and Treatment Options. In Vivo. 2021;35:681-91.

Ramos-Pascua LR, Sánchez-Herráez S, Alonso-Barrio JA, Alonso-León A. Osteocondromas solitarios del extremo proximal del fémur. Indicación y resultados de la resección en bloque sin luxación de la cadera [Solitary proximal end of femur osteochondroma. An indication and result of the en bloc resection without hip luxation]. Rev Esp Cir Ortop Traumatol. 2012;56:24-31. Spanish.

Inoue S, Noguchi Y, Mae T, Rikimaru S, Hotokezaka S. An external snapping hip caused by osteochondroma of the proximal femur. Mod Rheumatol. 2005;15:432-4.

Ghoti S, Mahajan NP, Kondewar P, Pande KP, Chaudhari K. A Case Report on Surgical Excision of Intracapsular Osteochondroma of Femur Neck using Mini-Arthrotomy without Hip Dislocation in a Young Female with Hereditary Multiple Exostoses. J Orthop Case Rep. 2022;12:66-9.

Yu K, Meehan JP, Fritz A, Jamali AA. Osteochondroma of the femoral neck: a rare cause of sciatic nerve compression. Orthopedics. 2010;33.

Makhdom AM, Jiang F, Hamdy RC, Benaroch TE, Lavigne M, Saran N. Hip joint osteochondroma: systematic review of the literature and report of three further cases. Adv Orthop. 2014;2014:180254.

Ratra R, Peshin C. Intra-articular Osteoid Osteoma Involving the Femoral Neck in Pediatric Population: A Case Report of 2 Cases. J Orthop Case Rep. 2022;12:73-6.

Xiao J, Lam SK, Shi Z, Zhou H, Luo X. Osteoid osteoma of the femoral neck causes deformity in children: a case report. Hip Int. 2011;21:490-4.

Schlesinger AE, Hernandez RJ. Intracapsular osteoid osteoma of the proximal femur: findings on plain film and CT. AJR Am J Roentgenol. 1990;154:1241-4.

Garg G, Malot R. Intra-articular Osteoid Osteoma of Femoral Neck Region: A Simplified Treatment Strategy and Review of Literature. J Orthop Case Rep. 2017;7:36-40.

Cerny J, Soukup J, Cerna S, Novotny T. Current Approaches to Osteoid Osteoma and Minimally Invasive Surgery-A Minireview and a Case Report. J Clin Med. 2022;11:5806.

Shi J, Zhao Z, Yan T, Guo W, Yang R, Tang X, et al. Surgical treatment of benign osteolytic lesions in the femoral head and neck: a systematic review. BMC Musculoskelet Disord. 2021;22:549.

Jaffe KA, Dunham WK. Treatment of benign lesions of the femoral head and neck. Clin Orthop Relat Res. 1990;134-7.

Banwart JC, Asher MA, Hassanein RS. Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. Spine (Phila Pa 1976). 1995;20:1055-60.

Barla M, Polirsztok E, Peltié E, Jouve JL, Legré R, Dautel G, et al. Free vascularised fibular flap harvesting in children: An analysis of donor-site morbidity. Orthop Traumatol Surg Res. 2017;103:1109-13.

Wisanuyotin T, Paholpak P, Sirichativapee W, Kosuwon W. Allograft versus autograft for reconstruction after resection of primary bone tumors: a comparative study of long-term clinical outcomes and risk factors for failure of reconstruction. Sci Rep. 2022;12:14346.

Kivioja AH, Blomqvist C, Hietaniemi K, Trovik C, Walloe A, Bauer HCF, et al. Cement is recommended in intralesional surgery of giant cell tumors: a Scandinavian Sarcoma Group study of 294 patients followed for a median time of 5 years. Acta Orthop. 2008;79:86-93.

Yuan Y, Liu Q, Liu Y, Wu Z, Zhong W, He H, et al. Comparative Analysis of Two Surgical Treatment Options for Giant Cell Tumor of the Proximal Femur: Extended Curettage and Segmental Resection. Front Oncol. 2021;11:771863.

Sakayama K, Sugawara Y, Kidani T, Miyawaki J, Fujibuchi T, Kamei S, et al. Diagnostic and therapeutic problems of giant cell tumor in the proximal femur. Arch Orthop Trauma Surg. 2007;127:867-72.

Abdulrazak S, Marzouki A, Bah ST, Lahrach K, Boutayeb F. Giant cell tumour of the femoral neck: Failure of curettage-cavity filling cementation with screw fixation, a case report. Trauma Case Rep. 2019;22:100216.

Luo S, Jiang T, Yang X, Yang Y, Zhao J. Treatment of tumor-like lesions in the femoral neck using free nonvascularized fibular autografts in pediatric patients before epiphyseal closure. J Int Med Res. 2019;47:823-35.

Carvallo PI, Griffin AM, Ferguson PC, Wunder JS. Salvage of the proximal femur following pathological fractures involving benign bone tumors. J Surg Oncol. 2015;112:846-52.

Evaluation of Cutaneous Drug Reactions due to Pirfenidone: A Histopathological Study and Management of Clinical Findings