Effective Use of Apremilast in Refractory Arthritis Associated With Cystic Fibrosis

To the Editor:

Arthritis is an infrequent but clinically impactful complication of cystic fibrosis (CF), adversely affecting patients’ quality of life.¹ Therapeutic management is complex due to the underlying disease, the high risk of infections, and potential pharmacological interactions with the intensive antibiotic regimens required for treating pulmonary infections.² Immunosuppressive therapy (IST) commonly prescribed for arthritis, including methotrexate and biologic agents, is often relatively contraindicated in patients with CF because they can further increase susceptibility to infection.³ A 2016 Cochrane systematic review concluded that no definitive conclusions can be made about the efficacy and safety of pharmacological agents for the symptomatic management of CF-related arthritis.⁴ Therefore, clinicians must carefully balance the potential benefits against possible risks in each case. Apremilast is an oral phosphodiesterase 4 (PDE4) inhibitor that modulates the inflammatory response by reducing the production of proinflammatory cytokines.⁵

Unlike traditional IST, apremilast exerts its effect by inhibiting PDE4, resulting in elevated intracellular cyclic adenosine monophosphate (cAMP) levels. This, in turn, downregulates the production of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-17, and other cytokines. The targeted modulation of inflammatory pathways allows apremilast to effectively mitigate inflammation while minimizing the broader immunosuppressive effects observed with conventional therapies. Consequently, apremilast is associated with a favorable safety profile, particularly concerning a reduced risk of opportunistic infections.⁶ It is approved for the treatment of psoriatic arthritis (PsA) and has shown efficacy in other inflammatory conditions.^7,8 However, its use in CF-related arthritis has not been widely studied.

Our patient is a 25-year-old female diagnosed with CF during childhood, presenting with recurrent pulmonary infections. The patient has never presented with pancreatic involvement or a significant decrease in lung function. Oropharyngeal and sputum cultures identified Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. She underwent continuous cycles of combined antibiotic therapy with 2 or 3 antibiotics based on culture sensitivities. The patient started ivacaftor therapy in June 2024, prescribed by an Italian pulmonology center specializing in the treatment of CF, with no substantial changes in the disease course observed a few months after treatment.

In 2017, the patient developed bilateral wrist arthritis. Radiographs did not reveal bone erosions or significant structural alterations. The arthritis was refractory to treatment with nonsteroidal antiinflammatory drugs (NSAIDs), systemic corticosteroids (prednisolone), and intraarticular corticosteroid injections. Given the risks posed by her chronic pulmonary infections and frequent antibiotic needs, traditional IST, such as disease-modifying antirheumatic drugs and biologic agents, was considered relatively contraindicated.

Serological analysis, including anticyclic citrullinated peptide antibodies, was negative, and the patient had no personal or family history of psoriasis. In December 2017, apremilast was initiated at a dose of 30 mg twice daily due to its immunomodulatory effects, which presented a potentially lower infection risk compared to traditional IST.

After 1 month of treatment, the patient reported complete resolution of joint symptoms. Prednisolone was discontinued, and there was no further need for NSAIDs or other antiinflammatory agents. The patient was monitored regularly over a 12-month period. During follow-up, there was no recurrence of arthritis, and no significant side effects attributable to apremilast were reported. Importantly, there was no increase in the frequency or severity of pulmonary infections during apremilast therapy. The patient continues combination antibiotic therapy for pulmonary infections at a frequency similar to that observed prior to starting apremilast.

Arthritis associated with CF is a rare inflammatory manifestation whose pathogenesis is not fully understood.⁹ Chronic inflammation, immune system dysregulation, and recurrent infections are thought to play key roles.² Therapeutic management is complicated by the need to avoid drugs that may suppress the immune system and exacerbate infection risks.³ Traditional IST used for arthritis, such as methotrexate and biologic agents targeting TNF-α, is associated with increased susceptibility to infections and is often relatively contraindicated in patients with CF.¹⁰ Whereas biologics, such as TNF inhibitors, have been documented in the management of CF-associated arthritis, the use of apremilast represents a novel therapeutic approach that has not been previously reported in the literature, underscoring the uniqueness of this case.¹¹

Apremilast, a selective PDE4 inhibitor, modulates the immune response by blocking the production of proinflammatory cytokines such as TNF-α, IL-17, and IL-23, while increasing antiinflammatory cytokines like IL-10.⁵ Its mechanism of action differs from that of traditional IST, potentially offering a safer profile in terms of infection risk.⁶ Clinical trials in PsA have demonstrated that apremilast has a lower incidence of serious infections compared to biologic agents.⁷ In the case of our patient, apremilast led to complete resolution of arthritic symptoms refractory to conventional treatments, without significant adverse effects or an increase in infection frequency. This outcome indicates that apremilast may represent a promising therapeutic option for patients with CF-associated arthritis where IST is relatively contraindicated due to high infection risks.

This case report presents several limitations that require consideration. First, as a single case, the findings cannot be generalized to the broader CF population. Additionally, randomized controlled trials are needed to rigorously establish the efficacy and safety of apremilast in CF-associated arthritis, particularly concerning infection risks.

Our case highlights the potential use of apremilast as an effective and safe therapeutic option for CF-associated arthritis. Apremilast may be a new strategy in managing arthritis in patients with CF in whom IST is relatively contraindicated due to high infection risks. However, further studies are required to confirm these findings and to develop clear therapeutic guidelines.

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