24. Chronic inflammatory arthritis in the context of cystic fibrosis
Authors: Clarke Elizabeth , Clegg Marie , Green Heather , Watson Pippa 
Published: September 2019

Abstract

Introduction
Cystic fibrosis (CF) is a genetic disease resulting in changes to the functioning of a transmembrane sodium transporter at mucosal surfaces and subsequent multisystem disease. Roughly 10,500 people in the UK live with CF, and life expectancy has improved markedly in the last few decades. Lung disease with bronchiectasis, chronic infection and progressive respiratory failure is accompanied by gastrointestinal, hepatic, pancreatic, and metabolic bone complications. An inflammatory arthritis known as cystic fibrosis associated arthritis (CFA), has been described in episodic and chronic forms for nearly 40 years now but remains without formal definition or an evidence base for treatment.

Case description
A 21-year-old woman with cystic fibrosis presented with a 4-year history of joint swelling and pain, initially affecting her fingers and then moving to knees and wrists and progressing from intermittent to chronic disease. Examination revealed active polyarthritis. Investigations included an ultrasound confirming active synovitis and blood tests showing negative rheumatoid factor, anti-CCP and HLA-B27.
Her past medical history included cystic fibrosis and vitiligo. She had a Ph508del homozygous genotype and her CF was characterised by severe bronchiectasis with Pseudomonas aeruginosa and Pandorea apista colonisation, severe airflow obstruction (FEV1 30% predicted), CF related diabetes requiring insulin therapy, exocrine pancreatic insufficiency, CF related liver disease, and low body mass.
She was diagnosed with an inflammatory arthritis felt likely to be a chronic form of cystic fibrosis associated arthritis. Hydroxychloroquine was commenced in November 2017 along with intramuscular corticosteroid which she had good but short lived response to. By December she had 14 tender and 5 swollen joints and had an acute exacerbation of her chest disease associated with a drop in FEV1 to 21% predicted and required IV antibiotics. Radiographs obtained at this point resulted in conflicting reports from radiologists about whether there was evidence of underlying periostitis in her distal radius and ulna, but it was decided that even if this represented hypertrophic periostitis secondary to CF lung disease then ongoing synovitis still required treatment with DMARDs.
A multidisciplinary decision was taken to commence sulfasalazine after admission for IV antibiotics. A portacath was present for IV access and, as such, bloods monitoring was carried out within the CF unit. Sulfasalazine was escalated to 1.5g daily alongside hydroxychloroquine. Whilst this has not completely eliminated all flares it has significantly improved day to day symptoms and has markedly limited number and severity of flares.

Discussion
The top differential diagnoses here include seronegative rheumatoid, chronic cystic fibrosis associated arthritis (CFA), and secondary hypertrophic osteoarthropathy (HOA).
CFA still has no formal definition and as such remains a diagnosis of exclusion in cases of inflammatory arthritis in the context of CF. It is unclear whether the more commonly seen episodic arthritis more frequently seen in CFA is part of a spectrum of disease that also includes chronic disease. Secondary HOA is reported in CF but the treatment evidence for this is also poor; X-rays are a poorly sensitive imaging modality for this; associated active synovitis still requires treatment.
Evidence for treatment of inflammatory arthritis in the context of CF is poor and concerns include risks associated with immunosuppression (especially in cases with severe bronchiectasis), polypharmacy, comorbid diabetes and liver disease. Some information may be extrapolated from case series of patients who have received a liver transplant for CF related liver disease but still have their native CF lungs suggesting that post-transplant levels of immunosuppression is relatively safe. A number of cases have reported safe use of biologics in CF for inflammatory arthritis or inflammatory bowel disease but there may be reporting bias. RA-bronchiectasis and RA-ILD cohorts provide some additional information but have a very different pathogenesis that may affect outcomes. Inflammation pathways are known to be impacted by CF but the differences are not yet informed enough to impact clinical decision making.
Sulfasalazine has provided a significant improvement in symptoms and in examination and ultrasound findings. We generally have not stopped it when courses of IV antibiotics have been required for exacerbations of chest disease, but would do so if systemic upset was present.

Key learning points
CF is a multisystem disease, in which life expectancy is increasing. Adult rheumatologists are likely to see more people with CF in their clinics over the coming decades with both CF related and non-CF related disease. They often have multiple associated comorbidities and a large burden of disease and treatment. They often attend their CF department with problems instead of the general practitioner and referrals may therefore come via respiratory consultants. Delays to treatment include a delay to presentation and delay whilst complex treatment decisions are taken. Supporting people with CF and inflammatory arthritis may include specific considerations regarding the need to carry out other treatments and an exercise regimen. Multidisciplinary and cross-specialty working is vital.
Making a formal diagnosis of a specific inflammatory arthritis in the context of CF can be difficult, but the definitive presence of inflammatory joint disease should prompt consideration of disease modifying drug therapy. Definite inflammatory arthritis may be easier to assess and image in a case such as this where the disease is chronic rather than episodic. Both clinical examination and ultrasound have a role in distinguishing it from non-inflammatory causes of musculoskeletal pain.
Immunosuppression in the context of CF is concerning. However, a growing but small body of evidence exists regarding safety. Pulling information from immunosuppression used for any indication in people with CF allows for better safety information to help teams and patients decide on the right treatment for them.

Conflicts of interest
The authors have declared no conflicts of interest.