Written by Dr Laura Durcan, Consultant Rheumatologist, Beaumont Hospital and Dr Wan Lin Ng, Specialist Registrar in Rheumatology, Beaumont Hospital
CASE of Rheumatoid Arthritis and Interstitial Lung Disease
A 56 year old gentleman was referred to our Rheumatology department in 2018 with pain, stiffness and swelling in his hands for several months. He reported pain and swelling in both metacarpophalangeal (MCP) joints and wrists. His past medical history included craniotomy and excision of right occipital arteriovenous malformation in 1989 with epilepsy secondary to this. He had a 20 pack-year smoking history and consumed 5 units of alcohol per week. He worked as a mechanic and did not have any family history of autoimmune conditions. The systems review was unremarkable.
On examination, he had active synovitis in bilateral second, third and fourth MCP joints with swelling of both his wrist joints. Initial blood results revealed raised inflammatory markers, negative Rheumatoid Factor (RF), strongly positive anti-cyclic citrullinated peptide antibody (ACPA) and negative anti-nuclear factor. Plain radiographs of his hands and feet showed mild osteopenia with no erosive changes.
This patient was diagnosed with seropositive Rheumatoid Arthritis and was commenced on methotrexate. A routine chest radiograph was ordered and revealed diffuse interstitial abnormalities most marked at the lung bases. This resulted in a chest CT which demonstrated evidence of bilateral subpleural reticulation, particularly in the bases which were in keeping with early fibrosis. There were two subpleural pulmonary nodules in the right lung. He was commenced on rituximab infusion but developed an allergic reaction to it.
He was referred to the respiratory team for management of his ILD. His chest CT images which were discussed at the lung multidisciplinary meeting (MDM) were consistent with a fibrosing non-specific interstitial pneumonitis (NSIP) pattern. He did not have any respiratory symptoms and his pulmonary function test revealed forced vital capacity (FVC) of 103% predicted and diffusing capacity for carbon monoxide (DLCO) was 93% predicted. He was strongly advised to stop smoking. A year later, he had a follow-up chest CT and the images from his most recent chest CT (Figure 1) were discussed at the lung MDM. The CT images showed a probable usual interstitial pneumonia (UIP) which had progressed from fibrotic NSIP. His right upper lobe nodule had progressed with central cavitation. CT guided biopsy of the nodule was advised to determine if the nodule is secondary to a rheumatoid nodule or malignancy.
He had several flare-ups while on the methotrexate, and sulfasalazine was commenced but the added therapy did not improve his symptoms. The patient had a great response when adalimumab was later added to his treatment regime.
Rheumatoid arthritis (RA) is an autoimmune condition characterised by chronic inflammation, particularly at the synovium leading to damage to the bone and cartilage causing profound disability. It affects approximately 1% of the population and is twice as common in women with peak incidence at 50 years. Patients diagnosed with Rheumatoid Arthritis typically present with symmetrical polyarthritis of the hands and feet for a period of several months, and is often associated with early morning stiffness. Rheumatoid Arthritis is also associated with extra-articular manifestations. These include episcleritis, scleritis, Sjögren’s syndrome, rheumatoid vasculitis, Felty’s syndrome and interstitial lung disease (ILD). Pulmonary involvement has become a major contributor to morbidity and mortality in RA-related deaths, second only to cardiovascular disease. Pulmonary involvement in Rheumatoid Arthritis can precede the onset of articular manifestations in up to 20% of the patients.
ILD is the most common pulmonary presentation in Rheumatoid Arthritis. Patients with RA-ILD present with symptoms such as breathlessness, cough, sputum production and fatigue. The median survival of patients with RA-ILD is estimated to be between 3-7 years.
RA-ILD is more prevalent in males, with a male to female ratio of 2:1 (despite RA being more common in females). History of smoking and advanced age are some of the risk factors for developing RA-ILD along with high titres of RF and ACPA. 3-15% of patients with RA are found to have the presence of anti-Ro/SSA antibodies. A retrospective study demonstrated that 60.4% of patients with RA who had positive anti Ro-52 antibodies and 20% with isolated anti Ro-60 antibodies developed ILD. Interleukin-1-alpha antibody, KL-6 glycoprotein, interferonγ-inducible protein and matrix metalloproteinase-7 are some serum markers that are linked with RA-ILD. Recent studies have shown that the presence of the MUC5B variant could increase the risk of developing ILD in patients with RA. Another study demonstrated a higher risk for RA-ILD in those who carry HLA-DRB1*1502.
Investigation into Rheumatoid Arthritis
As patients with RA have approximately a 10% lifetime risk of developing RA-ILD, patients presenting with respiratory symptoms should have a thorough physical examination and relevant investigations. Pulmonary function tests (PFTs) are commonly used to screen and monitor disease activity in patients with RA-ILD. It is important to note that normal PFT results can be present in early ILD and this does not rule out mild pulmonary disease. Patients with ILD can have reduced diffusion capacity for carbon monoxide (DLCO), followed by reduced flow (forced vital capacity [FVC]) and reduced lung volumes (total lung capacity [TLC]) in more advanced diseases. A decline of ≥10% in FVC or ≥15% in DLCO likely indicates worsening ILD. The 6-minute walk test (6MWT) is a simple measure that provides prognostic information in patients with established RA-ILD.
Chest radiography is a cheap and readily available tool to identify pleural effusions and pneumonia but has poor sensitivity and specificity for detecting ILD. High resolution computed tomography (HRCT) is used to diagnose and monitor the disease progression in ILD. Prognosis is guided by the extent of fibrosis demonstrated on HRCT and the various subtypes. Usual interstitial pneumonia (UIP) pattern which is characterised by basilar and subpleural reticulation with or without traction bronchiectasis and honeycombing is the most common subtype in RA-ILD, followed by nonspecific interstitial pneumonia (NSIP) which has a predominantly ground-glass appearance. Other RA-ILD subtypes include organising pneumonia (OP), lymphocytic interstitial pneumonia (LIP), acute interstitial pneumonia, desquamative interstitial pneumonia and respiratory bronchiolitis ILD. Bronchoalveolar lavage (BAL), although not routinely performed in this condition, may be helpful to evaluate the activity of the development processes in RA- ILD and to out rule infections, malignancy and haemorrhage. Surgical lung biopsy is less commonly performed in recent years to diagnose ILD as HRCT is a very reliable diagnostic tool.
Treatment of Rheumatoid Arthritis
Patients with RA-ILD can be managed with immunosuppressive therapy. Patients with NSIP, OP or LIP generally respond better to corticosteroids compared to the more fibrotic patterns such as UIP and fibrotic NSIP. Rituximab, which is an anti-CD20 monoclonal antibody, has been used in the treatment of RA-ILD. The RECITAL study is an ongoing multicenter, prospective, randomised, doubleblind, controlled trial of rituximab versus cyclophosphamide to study the efficacy of rituximab in patients with connective tissue disease related ILD (CTD-ILD) which would provide great insights once completed. Results from the focuSSced study demonstrated a favourable change in FVC percentage predicted in patients with SSc-ILD treated with tocilizumab. Tocilizumab is an IL-6 receptor antibody that is commonly used in RA and further studies should be conducted to see its role in patients with RA- ILD. Abatacept, which is a fully humanised monoclonal antibody against CD80/86 was associated with stabilisation of FVC in a multicenter, open-label study of patients with RA-ILD.
Nintedanib is a tyrosine kinase inhibitor that has been shown to slow the progression of disease progression in patients with idiopathic pulmonary fibrosis (IPF) and also in patients with scleroderma related ILD in the recent SENCSIS trial. The annual rate of decline in FVC was shown to be much less with nintedanib compared with placebo in patients with SSc-ILD in the SENSCIS trial. The INBUILD trial had demonstrated the role of nintedanib in slowing the rate of decline in FVC in patients with CTD-ILDs. Pirfenidone, another anti-fibrotic agent which acts on the regulation of TGF-5 activity, TNF-α and β pathways, as well as cellular oxidation has also been proven to slow down disease progression in IPF. Ongoing studies such as the TRAIL study are being carried out to demonstrate the efficacy of these antifibrotics in patients with connective tissue disease related ILD. As shown in most literature, the main limiting factor of patients continuing on nintedanib or pirfenidone is their gastrointestinal side effects which include diarrhoea, nausea, vomiting and abdominal pain. It is worth noting that leflunomide, which is generally used in the treatment of RA should be avoided when co-prescribing with nintedanib or pirfenidone due to their elevated risk of raised liver enzymes.
The option for lung transplantation should be considered for younger patients with end-stage RA-ILD. The consideration for a lung transplant is generally complicated with advanced age, immobility and multiple comorbidities. The post lung transplantation outcomes in patients with RA-ILD are comparable to patients with IPF with one-year survival post lung transplant of 67% and 69% respectively.
Adjunctive measures are recommended in addition to the traditional immunosuppressive therapies for the management of RA-ILD. Patients should be advised to smoke cessation, be enrolled on pulmonary rehabilitation therapy, receive supplemental oxygen therapy and ensure appropriate vaccination such as pneumococcal, influenza and COVID-19 vaccinations. Early palliative care intervention in this cohort of patients is increasingly important to improve patients’ symptoms, quality of life and caregivers’ psychosocial needs.
ILD is an increasingly important clinical manifestation in patients with Rheumatoid Arthritis. It remains challenging to manage patients with RA-ILD due to the paucity of data and the complex nature of the disease. Immunosuppressive therapy, antifibrotics and a multidisciplinary approach are important measures in the treatment of RA-ILD.
References available on request
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