Rheumatoid arthritis in a patient with cystic fibrosis: challenging treatment options

Abstract

A 26-year-old Caucasian male patient with a history of cystic fibrosis presented with a 6-month history of diffuse joint pain and swelling. He was found to have active synovitis in bilateral wrists and proximal interphalangeal joints of the hands on physical examination. He was diagnosed with seropositive rheumatoid arthritis since he had positive anti-cyclic citrullinated peptide antibodies and erosions on hand and foot X-rays. The patient has responded well to abatacept which may have less infection risk compared with other biological therapies.

Background

Patients with cystic fibrosis (CF) can have varied articular manifestations. Distinguishing between CF arthropathy (CFA) and other rheumatologic conditions, such as rheumatoid arthritis (RA), can be challenging. History, physical examination, laboratory studies and imaging can help establish the diagnosis. Treatment of arthritis in these patients can be difficult as patients with CF often have lung abnormalities and frequent infections. RA treatments can be associated with increased risk of infections. Particularly methotrexate, a cornerstone of RA therapy, can rarely cause lung toxicity. Use of methotrexate in the presence of pre-existing severe lung disease is typically avoided. Degree of lung disease, infectious history and severity of articular manifestations should all be taken into account when choosing therapy for arthritis in CF.

Case presentation

A 26-year-old Caucasian male patient with CF presented in 2015 with a 6-month history of diffuse arthritis affecting his bilateral wrists, hands, knees and feet. Pain and swelling would last a few days before resolving. Symptoms would improve with the use of non-steroidal anti-inflammatory drugs (NSAIDs) and heat. He was experiencing a flare of these symptoms three to four times per month. He had morning stiffness lasting 2 hours. He denied any fevers, vision changes or eye symptoms, recent infections (including gastrointestinal and genitourinary), rashes, oral ulcers, alopecia, chest pain, shortness of breath and fatigue. He has never smoked or used any illicit drugs.

Musculoskeletal examination was significant for active synovitis in bilateral wrists and proximal interphalangeal joints of the hands. He had tenderness in bilateral second, third and fourth metacarpophalangeal joints. Bilateral foot examination with positive metatarsophalangeal squeeze test without appreciable synovitis. Grip strength was decreased bilaterally. Pulmonary and cardiovascular examinations were normal. No rashes were observed.

The patient was diagnosed with CF at infancy and has a delta F508 homozygous mutation. His disease has been complicated by pancreatic insufficiency, malnutrition, low body mass index, chronic sinus disease and Pseudomonas colonisation.

Investigations

Rheumatoid factor (RF) was normal at 20 units/mL. Anti-cyclic citrullinated peptide (anti-CCP) antibodies were positive at 71 units (normal range 0–19 units). Antinuclear antibody was negative. C reactive protein was elevated at 34.6 mg/L (normal range <2.0 mg/L). Complete blood counts, creatinine, liver function tests and uric acid were all normal.

Radiographs of bilateral hands revealed radiocarpal, intercarpal and carpometacarpal joint space loss. Erosions were seen within the capitate, hamate, trapezoid, ulnar styloid process, first metacarpal phalangeal and base of the index metacarpal (figure 1). Radiographs of bilateral feet revealed erosions in the second, third, fourth and fifth metatarsal heads (figure 2).

Figure 1.

Radiocarpal, intercarpal and carpometacarpal joint space narrowing is present. Erosions were seen in the carpal bones, ulnar styloid, right first MCP and base of the second metacarpal (see pink outlined arrows). Soft tissue swelling is noted at left third PIP, right first MCP and right second PIP (see blue arrow). MCP, metacarpophalangeal; PIP, proximal interphalangeal.

Figure 2.

Extensive erosions are seen at bilateral fifth metatarsal heads.

CT chest showed bronchial wall thickening and mild bronchiectasis with subtle areas of cylindrical bronchiectasis. Subtle tree in bud opacities, scattered centrilobular nodules and areas of subsegmental atelectasis were also seen. The pancreas was noted to have diffuse fatty infiltration. These findings are consistent with CF (figure 3).

Figure 3.

CT chest showed bronchial wall thickening and mild bronchiectasis with subtle areas of cylindrical bronchiectasis. Subtle tree in bud opacities, scattered centrilobular nodules and areas of subsegmental atelectasis were also seen.

Differential diagnosis

The articular manifestations of CF are ill defined and vast in its range of presentations; refer to box 1 for a differential.

Box 1. Rheumatic manifestations reported with cystic fibrosis.

• Amyloidosis (secondary)

• Bowel disease-associated arthritis

• Cystic fibrosis arthropathy (recurrent bouts of painful monoarthritis or polyarthritis)

• Quinolone-induced arthropathy

• Hypertrophic pulmonary osteoarthropathy

• Juvenile idiopathic arthritis

• Non-specific musculoskeletal manifestations (costochondritis, patellofemoral pain syndrome, strains and so on)

• Rheumatoid arthritis (seropositive or seronegative symmetric polyarthritis)

• Osteopenia

• Osteoporosis

• Vasculitis

RA can occur in patients with CF. However, the differential can also include CFA, reactive arthritis, psoriatic arthritis, quinolone-associated arthritis, hypertrophic pulmonary osteoarthropathy (HPOA) and crystalline arthritis. Crystalline arthritis should typically be episodic, asymmetric and monoarticular or oligoarticular involvement. The pattern of joint involvement and lack of hyperuricemia in our patient makes crystalline arthritis less likely. Reactive arthritis should also be considered especially given the high propensity for chronic Pseudomonas aeruginosa pulmonary colonisation in patients with CF. Typically, these patients will improve with antibiotic therapy. Our patient had persistent arthritis despite adequate antibiotic treatment for his pulmonary infections. CF patients can suffer from chronic pulmonary infections that require prolonged courses of fluoroquinolone therapy. As a result, some of these patients develop quinolone-induced arthropathy. However, this does not apply to our patient who had persistent arthritis despite not being on quinolone therapy in years. HPOA is characterised as long bone periostitis and pain.^{1 2} The most common clinical presentation is a symmetrical polyarthritis with effusions present in the wrists, knees and ankles.^{1 2} HPOA flares are often associated with new pulmonary infections.^{1 2} Therefore, treatment for HPOA focuses on improving pulmonary function and antibiotic treatment.^{1 2} Our patient had persistent arthritis despite antibiotic therapy and stable pulmonary function. CFA is a diagnosis of exclusion and does not have clear diagnostic criteria. This disease can be monoarticular or polyarticular and have a recurrent, self-limiting course or be a chronic, progressive disease.^{1 2} Classically, CFA is categorised as a non-erosive arthritis of large monoarticular joints, particularly the knee; however, bilateral small joint synovitis is also frequently described in the literature.^{1 2} In the CF population, non-specific RF elevation is a common occurrence.¹ Anti-CCP has frequently been referenced as a marker to help delineate CF patients with corresponding RA.³ Given our patient’s clinical presentation and positive anti-CCP, RA was diagnosed. At time of his initial evaluation, his Disease Activity Score 28-joint count C reactive protein (DAS28-CRP) Score was 5.42, indicating high disease activity.

Treatment

The patient was initially treated with a prednisone taper after diagnosis in 2015 which greatly improved his symptoms. Given concerns for infection in the setting of CF, prednisone was tapered down and he was started on hydroxychloroquine 200 mg two times per day in 2015. Since he continued to have joint pain and swelling, leflunomide was added in the same year, which enabled him to taper off prednisone completely. The patient began having significant unintentional weight loss (30 lb in 3 months) which was ultimately felt to be secondary to leflunomide, so this was discontinued 3 months after initiation. Minocycline was tried for a few months in 2016 but was discontinued due to lack of efficacy. He was started on abatacept 125 mg subcutaneous every week due to progression of joint pain, swelling and new erosions seen on X-ray in 2018. After initiation of treatment, DAS28-CRP Score improved to 2.49. Throughout this course, the patient would also take intermittent NSAIDs as needed.

Outcome and follow-up

The patient has been on abatacept for more than a year. He has had significant improvement in joint stiffness, pain and swelling. His weight stabilised, appetite improved and he is no longer using NSAIDs frequently. He has had one course of antibiotics for a Pseudomonas pulmonary infection in the last year. He has not required hospitalisation for infection since starting abatacept. His RA disease activity has been well controlled on the combination regimen of hydroxychloroquine and abatacept.

Discussion

Patients with CF can have a variety of musculoskeletal symptoms that can be associated with or independent from their pulmonary disease process. Some of these patients can have coexisting RA, which can be difficult to treat given their underlying pulmonary pathology and high propensity for recurrent infections. A Medline search was conducted using the keywords ‘cystic fibrosis’, ‘rheumatoid arthritis’, ‘arthritis’, ‘musculoskeletal’, name of individual biological agents and conventional disease-modifying antirheumatic drugs (DMARDs). Table 1 summarises the case reports which have described treatment of RA in patients with CF. DMARDs may be inadequate at controlling their articular symptoms. In addition, DMARDs may have side effect profiles that limit their use, such as methotrexate raising concerns for pulmonary adverse effects. There have been case reports documenting successful use of biological therapies in the CF patient population. However, there is concern for a higher risk of infection given their chronic pulmonary bacterial colonisation.

Table 1.

Case reports on RA treatment options in cystic fibrosis patients

Case series	Year	Presentation	Serologies	Treatment failures	Treatment success	Treatment complications
Visser et al9	2012	Polyarticular synovitis for 2 years, olecranon rheumatoid nodules	RF positive, CCP positive	NSAIDs, HCQ, steroids, MTX	Etanercept, MTX	None
Adelsten et al10	2015	Oligoarticular synovitis for 3 years	RF negative, CCP negative	Steroids, MTX, salazopyrine, HCQ	Etanercept, MTX, steroid*	None†
Casserly et al11	2009	Symmetric small joint polyarticular synovitis for 5 years	Not available	LEF, NSAIDs	Infliximab	Two CF exacerbations in 8 years
Sagransky et al12	1980	Diffuse, symmetric polyarticular synovitis, olecranon rheumatoid nodule	RF positive, CCP not available	NSAIDs, ASA, gold sodium thiomalate	HCQ	Proteinuria secondary to gold therapy
Gardiner et al13	1988	Diffuse symmetric polyarticular synovitis, olecranon rheumatoid nodule	RF positive CCP not available	Not available	Not available	Not available

*Low dose prednisolone.

†Patient was receiving intravenous anti-Pseudomonas treatment every 3 months prophylactically.

ASA, aspirin; CCP, cyclic citrullinated peptide; CF, cystic fibrosis; HCQ, hydroxychloroquine; LEF, leflunomide; MTX, methotrexate; NSAIDs, non-steroidal anti-inflammatory drugs; RA, rheumatoid arthritis; RF, rheumatoid factor.

We decided to start a biological agent since our patient continued to have progressive, erosive disease, persistent, significant joint pain and swelling and intolerance or inadequate response to conventional DMARDs and NSAIDs. After discussion with the patient and the pulmonologists, we selected abatacept since some studies have suggested lower risk of infection in comparison to other biological agents.^4–6 Yun et al reported lower 1 year risk of infections requiring hospitalisation among patients who received abatacept when compared with those who received etanercept, infliximab or rituximab.⁴ This was a retrospective cohort study containing 31 801 new biological treatment episodes among Medicare enrolled patients in the USA with RA between 2006 and 2011 who had been newly prescribed etanercept, adalimumab, certolizumab pegol, golimumab, infliximab, abatacept, rituximab or tocilizumab.⁴ More recently, Chen et al conducted a propensity score-matched cohort study to assess the risk of hospitalised infections among RA patients who were being started on biologics.⁵ Using medical and pharmacy claims data between 2006 and 2015 on commercially insured individuals across the USA, they identified 11 248 propensity score-matched pairs of patients who were treated with abatacept or tumor necrosis factor (TNF) antagonists.⁵ Even though they reported less risk of infections with abatacept, most of the increased risk found with TNF antagonists was from infliximab since no significant difference was seen in comparison to etanercept or adalimumab.⁵ However, they noted lower risk of pulmonary infections with abatacept.⁵ Ozen et al reviewed patients from the National Databank for Rheumatic Diseases (FORWARD) during the years spanning from 2005 to 2015 and compared those on abatacept versus an alternative regimen of either a biological or conventional DMARD.⁶ The study sampled the initiation of 1496 patients on abatacept, 3490 on another biological DMARD and 1520 on a conventional DMARD.⁶ Patients receiving abatacept were found to have a statistically significant lower rate of hospitalised infections when compared with alternative biological DMARDs.⁶

Our patient has experienced significant improvement in this RA activity with abatacept and had only one minor infection that did not require hospitalisation. However, this may be coincidental since other studies have reported the risk of infections with abatacept may be similar to other biologics.^{7 8} George et al demonstrated among 9911 RA patients undergoing 10 923 arthroplasties that there is similar risk for infectious complications when comparing TNF-alpha antagonists, interleukin-6 (IL-6) blockers, anti-CD20 monoclonal antibodies and abatacept.⁷ When specifically evaluating abatacept as an initial biological agent for the treatment of RA, Montastruc et al found there to be no statistically significant difference in the rate of infections when comparing to other biologics (TNF-alpha inhibitors, IL-1 antagonist, CD20 monoclonal antibody, IL-6 antagonist and Janus kinase inhibitor).⁸

In conclusion, CF can present with various rheumatic manifestations, including symmetric polyarthritis mimicking RA. Although there is increased risk of infection with immunosuppressive therapies, DMARDs and/or biologics can be used judiciously.

Patient’s perspective.

When I was first diagnosed with rheumatoid arthritis, I struggled largely doing everyday tasks including showering, getting dressed, walking and sleeping due to swelling and joint pain in hands, shoulders, knees and feet making it extremely difficult to use my hands or raise my arms. I am an avid drag racer and the pain that I had made me struggle to get in and out of my car at the track and due to that it reduced how often I could go because sometimes I just did not feel up to it. About 1 month after starting Orenica, I woke up and did not feel the pain that I was used to having. I could now sleep through the night without hurting and can do more of my everyday tasks that I was unable to do before and feel more like my normal self again. I have been on Orencia about 1 year now and have greatly improved since starting it.

Learning points.

• Cystic fibrosis can be associated with various rheumatic manifestations including symmetric polyarthritis as seen in rheumatoid arthritis.

• Despite the increased risk of infection with immunosuppressive therapies, disease-modifying drugs and/or biologics can be used judiciously.

• Among the biologics, abatacept may be associated with less risk of infection.