Abstract
INTRODUCTION: Pirfenidone is a promising antifibrotic agent used in the treatment of idiopathic pulmonary fibrosis (IPF). Although its exact mechanism is not fully understood, it modulates fibrogenic growth factors and suppresses transforming growth factor-beta 1 (TGF-β1), reducing fibroblast proliferation, myofibroblast differentiation, and extracellular matrix deposition. As a relatively new medication, its complete side effect profile is still being established. Commonly reported adverse effects include arthralgia, musculoskeletal chest pain, and myalgia. However, there is no documented evidence in the current literature linking pirfenidone to worsening myopathy or elevated creatine kinase (CK) levels. CASE DESCRIPTION: A 70-year-old Caucasian gentleman with a history of myocardial infarction in 2015 was commenced on statins, which resulted in persistent statin-associated muscle symptoms. Due to intolerance, statins were discontinued in 2019 and replaced by inclisiran injections every six months. His regular medications included ramipril 5 mg, ezetimibe 10 mg, aspirin 75 mg, and bisoprolol 2.5 mg. In April 2024, he was referred to the respiratory team for progressive dyspnoea. High-resolution CT demonstrated a usual interstitial pneumonia (UIP) pattern. Autoimmune screening (RF, ANA, MPO, PR3) was negative. Blood tests revealed an elevated creatine kinase (CK) of 1908 U/L, mild hypergammaglobulinemia (IgG 16.6 g/L), and raised ALT (61 U/L). Pirfenidone was initiated in August 2024. Subsequently, he developed worsening myalgias and elevated liver enzymes (ALT, ALP). Ezetimibe was discontinued, followed by pirfenidone in February. In March 2025, he developed profound proximal muscle weakness, elevated CK (14,000 U/L), and further liver dysfunction. He was hospitalised and evaluated by neurology. Investigations revealed immune-mediated necrotising myositis on muscle biopsy; MRI showed diffuse acute moderate-to-severe myositis; PET was negative for malignancy but supportive of widespread low-grade inflammation. Antibody testing was positive for anti-HMGCR and borderline for anti-TIF1γ. The findings were consistent with immune-mediated necrotising myopathy (IMNM), likely HMGCR-positive subtype. Prednisolone 50 mg daily was initiated with gradual tapering. After three months, clinical improvement was noted with CK reduced to 1922 U/L. Pirfenidone was cautiously reintroduced. However, a subsequent CK rise to 2552 U/L and recurrence of muscle aches led to the discontinuation of pirfenidone again. DISCUSSION: IMNM has emerged as a distinct entity within the spectrum of idiopathic inflammatory myopathies (IIMs). It is histologically characterised by abundant necrotic muscle fibres and minimal perivascular inflammation, often associated with the presence of anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies. The majority of IMNM cases present with a subacute onset (within six months), representing approximately two-thirds of patients, while about one-fourth experience chronic disease progression over more than 12 months. A hallmark clinical manifestation is proximal muscle weakness, observed in 86.8–99.1% of cases, with lower limb involvement being the most commonly reported. Serum creatine kinase (CK) levels are typically elevated. Statin-induced rare side effects are variable and have been reported in the literature to include interstitial lung disease with pleural effusion and myopathy. Discontinuation of the statin alone often does not lead to symptom resolution. In many cases, immunosuppressive therapy is required to achieve a clinical response. This raises the suspicion that our patient’s lung disease may be associated with prior statin use. A comprehensive review of the literature did not identify any established pharmacological interaction or shared metabolic pathway between pirfenidone and the patient’s concurrent medications. The situation was further complicated by the incompletely understood mechanism of action of pirfenidone. Nevertheless, a temporal association was noted muscle pain and elevated CK levels recurred upon re-initiation of pirfenidone, strongly implicating its role in exacerbating the underlying myopathy. We present what we believe to be the first reported case of pirfenidone-associated exacerbation of IMNM in the setting of HMGCR-positive myositis. This case was uniquely challenging, as the patient lacked a formal diagnosis of HMGCR myopathy before initiating pirfenidone therapy. However, the patient had a documented history of statin-induced muscle pain accompanied by elevated CK levels, raising clinical suspicion of HMGCR-related myopathy. KEY LEARNING POINTS: This case report would appear to be the first in the literature to document worsening of IMNM due to pirfenidone. For patients with a diagnosis of IIM/IMNM, close monitoring of CK levels and clinical deterioration should be considered for patients who are concurrently prescribed pirfenidone. The effective management of patients with complex medical needs requires integrated, multidisciplinary collaboration to optimise clinical outcomes. Pirfenidone, a relatively novel antifibrotic agent with an incompletely understood mechanism of action, necessitates close monitoring for adverse effects. The emergence of new symptoms following its initiation should prompt consideration of potential drug-related toxicities. In cases where patients present with elevated alanine aminotransferase (ALT) levels and concurrent myalgias, further investigation is warranted to rule out rhabdomyolysis and underlying inflammatory myopathy. Notably, for patient on statin therapy, discontinuation of statins may not yield complete resolution of symptoms. Immunosuppressive treatment is often required to achieve meaningful clinical improvement. Anti-HMGCR-positive myopathy represents a recently characterised autoimmune muscle disease, marked by diverse clinical manifestations. Given its variable presentation, clinicians should maintain a broad differential diagnosis and approach assessment with diagnostic flexibility.