Interstitial Lung Disease in Rheumatoid Arthritis: A Clinical Dilemma

Rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is an increasingly common extra-articular cause of mortality and morbidity in RA. Here, we present the case of an 82-year-old female suffering from RA-ILD. She presented with a 20-year history of RA with new-onset progressively worsening dyspnoea, pyrexia, and dry cough, which were not responsive to initial antibiotics. Moreover, she had been on long-term methotrexate, which can cause pulmonary disease. Investigations revealed raised inflammatory markers, restrictive lung patterns, and radiological features of ILD. She was treated with a tapering course of oral prednisolone and home oxygen, which provided some symptomatic improvement. Diagnosis of RA-ILD can be challenging due to several contributing factors. Optimal treatment is controversial, and corticosteroids have been widely used but with limited effects. There is evidence directed at potential therapeutic benefit from a number of newer agents, which are discussed. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISBN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, 2014, 22(1): 88-101. doi:10.2218/resmedica.v22i1.732. Res Medica 2014, Volume 22, Issue 1 Tan, TSE. Interstitial Lung Disease in Rheumatoid Arthritis: A Clinical Dilemma. Res Medica 2014, 22(1), pp. 88-101. doi:10.2218/resmedica.v22i1.732 88 Interstitial Lung Disease in Rheumatoid Arthritis: A Clinical Dilemma


Introduction
It is estimated that nearly half of patients with rheumatoid arthritis (RA) will develop some form of associated respiratory complication in their lifetime. 13] Moreover, the medications used in treating RA can cause respiratory toxicity and this can complicate diagnosis.Despite several recent promising developments, the understanding of RA-ILD is not well established and its management has not been clearly defined.In light of this, we report a case of RA-ILD that presents a clinical dilemma.

Case Summary
An 82-year-old female presented with a 2week history of new-onset progressively worsening dyspnoea (both on physical exertion and at rest), pyrexia (37.8°C), and dry cough.The predictors for RA-ILD include smoking, 5- 6 male sex, 7 long duration of disease, and the presentation of systemic features such as fever and weight loss. 8Moreover, increased polymorphisms at the HLA-B40 and HLA-B54 antigen sites have been found in RA-ILD and cryptogenic organizing pneumonia (COP). 9-10[13] Methotrexate-induced ILD Methotrexate, the first-line disease-modifying antirheumatic drug (DMARD) in treating RA, is known to cause methotrexate-induced pulmonary toxicity, of which methotrexate pneumonitis (inflammation of lung tissue) is common, 14 and this can progress to pulmonary fibrosis. 15The most significant risk factor for developing pneumonitis is preexisting pulmonary disease, coupled with a baseline diffusing capacity of < 70% predicted, which increases the risk of developing methotrexate drug toxicity 10-fold. 16Other risk factors are listed in Table 2.

She was initially treated for community-
Lung toxicity often occurs after weeks to months of low-dose oral methotrexate therapy, which has been associated with a possible 20% increased mortality rate if toxicity occurred within first 6 months of treatment. 17In about 90% of patients with methotrexate-induced pulmonary toxicity, low grade fever has been reported.Also, approximately 80% of patients presented with a dry, non-productive cough and dyspnoea on exertion. 17nce, methotrexate should be carefully considered in patients with prior RA-ILD 18 due to the increased susceptibility of developing pneumonitis, even though methotrexate does not directly exacerbate ILD. 19

Diagnosis of ILD
A thorough clinical evaluation is necessary in RA patients presenting with respiratory symptoms 18 (Figure 3).This is followed by a chest radiograph and PFTs to rule out common respiratory conditions like infection.
8] Once the diagnosis of ILD is made, the challenge of determining its aetiology arises, especially in the event of an acute clinical decline in lung function.If in diagnostic doubt, a videoassisted thoracoscopic surgery (VATS) biopsy should be considered to determine histology. 29 the case of methotrexate pneumonitis, a diffuse interstitial pattern on HRCT has been reported in more than 93% of patients; pleural thickening and, less commonly, pleural effusions are seen in a small number of patients. 17 20 In essence, all infective complications have to be investigated thoroughly and managed with the necessary cessation of immunosuppressive therapy and commencement of the relevant antibiotics according to the results of routine blood, urine, and BAL cultures.

Management of RA-ILD
According to the British Thoracic Society (BTS) guidelines published in 2008, 23 the initial treatment of RA-ILD is typically with oral prednisolone at an initial dose of 0.5-1 mg/kg/day over a period of 1-3 months.This is then tapered down to a maintenance dose of 10 mg/day or 20 mg on alternate days and administered with immunosuppressants such as cyclophosphamide, 35 azathioprine, 36 penicillamine, 36 or methotrexate according to clinical response.Immunosuppressants have to be evaluated in line with response to steroids.
Cyclophosphamide has been found to be therapeutic in methotrexate-induced pneumonitis that has not been responsive to the usual methotrexate discontinuation, oxygen therapy, and/or corticosteroids. 38e to the lack of controlled studies, optimal treatment of RA-ILD remains a matter of debate.A recent update on the management of RA-ILD suggests that patients can be broadly divided into 3 groups based on the extent of their disease, and this determines their treatment 40   survival. 42The majority of patients with RA-ILD have either UIP or NSIP. 21UIP conveys the worst prognosis, 43,44 whereas patients with NSIP carry a better prognosis and response to treatment, with the cellular subtype associated with higher survival rates as compared to the fibrotic subtype.COP (rarer) also displays a better prognosis and is more responsive to oral corticosteroid therapy.

Learning Points
What is known already known  ILD is strongly associated with Rheumatoid Arthritis and its anti-rheumatic medications, such as methotrexate.
 ILD is usually treated with a tapering course of corticosteroids and/or immunosuppressants and managed holistically with ancillary treatments.

What this study adds
 The inclusion of a number of new agents (e.g.mycophenolate mofetil, rituximab, and cyclophosphamide) has provided a better outlook in treating ILD.Thorough consideration must be given to each individual patient's extent of disease, rate of progression and co-morbidities when deciding which treatments to administer.
 Prompt treatment delays disease progression of RA-ILD of arthritis and management revolves around symptom control.
 Multidisciplinary holistic care ensures best practice.
had been taking 15 mg of methotrexate once weekly for 15 years, which was subsequently stopped.She has no known drug allergies and is also on regular prescriptions of folic acid, calcium tablets, naproxen, and alendronate sodium for her musculoskeletal problems -long-standing seropositive RA (20 years), osteoarthritis, and osteoporosis -which have been well controlled.She is a non-smoker and is normally mobile and active without any known respiratory problems.There were no previous exposures to asbestos or industrial chemicals but she kept cockatiels at home for years.On clinical examination, lower lobes of the lungs were dull on percussion and bilateral inspiratory basal crackles were heard on auscultation with decreased air entry into both lower lobes.Her respiratory rate was 28 breaths/minute.Rheumatoid changes were also noted on her hands but without any digital clubbing.Laboratory workup revealed the following:  Haemoglobin -11.1 g/dL (↓)  White cell count -16.2 × 10 9 /L ( ↑ ) (no evidence of eosinophillia)  Platelets -425 × 10 9 /L (↑)  INR -1.4 (↑)  C-reactive protein -156.9 mg/L (↑). Arterial blood gaseso pH=7.509(↑), o PO2=6.69 kPa (↓) o PCO2=4.7 kPa o HCO3 − =28.2 mmol/L o Base excess = 4.5 mmol/L (↑) In addition, her pulmonary function tests (PFTs) revealed a restrictive pattern, with a reduced diffusing capacity and carbon monoxide transfer coefficient (Kco).Her oxygen saturation was 78% on room air.A chest radiograph (Figure 1 with white arrows) revealed increased bilateral patchy airspace shadowing as compared to imaging performed 2 years earlier.Additionally, a high-resolution computed tomography (HRCT) scan of the thorax (Figure 2) showed bilateral basal honeycombing with peripheral patchy ground-glass opacification (white arrows) and traction bronchiectasis (black arrows).The overall clinical picture was consistent with interstitial lung disease (pulmonary fibrosis) secondary to either rheumatoid arthritis (RA-ILD) or with possible superimposed methotrexate-induced pneumonitis.Other differential diagnoses considered were aspiration pneumonia, pneumocystis infection, acute exacerbation of an existing ILD, and hypersensitivity pneumonitis (cockatiel exposure).She was treated with a tapering course of oral prednisolone (20 mg once daily on discharge for 4 weeks, followed by 15 mg, then 10 mg) and 4 L/minute of home oxygen.On latest follow-up, her oxygen saturations improved to 97% on 2 L of oxygen.However, PFT results remained largely unchanged.

(Figure 4 )
, which is generally directed at disease control and treatment corresponding to histopathologic subtype.The first group comprises patients with asymptomatic ILD, whose pulmonary function and symptoms have to be monitored closely.If these are stable with no evidence of disease progression, then no specific therapy is indicated.The second group of patients includes those who are initially stable and asymptomatic but later experience progressive chest symptoms and a decline in lung function.Notably, most of these patients will still display limited disease signs on baseline HRCT.For this group, treating their pulmonary condition, in addition to a single or combined DMARD therapy for their joint disease, is the priority.If severe articular disease (disease activity score (DAS28) > 5.1) is evident, patients may benefit from biologic agents such as rituximab.In the absence of severe articular disease, the use of mycophenolate mofetil (1-2 g once daily) with or without acetylcysteine (600 mg three times daily) has been recommended.The final group of patients are those with rapidly progressive or extensive RA-ILD involving more than 20% of the lungs.The first-line treatment is 6 cycles of intravenous cyclophosphamide 10-15 mg/kg in combination with methylprednisolone 7-10 mg/kg at 4-6-week intervals.Occasionally, mesna is prescribed to reduce the risk of haemorrhagic cystitis and later on, bladder cancer as a result of urothelial toxicity from cyclophosphamide therapy.Co-trimoxazole prescribed as prophylaxis against pneumocystis pneumonia, and anticoagulation is commenced in patients with proven pulmonary embolism.Lung function has to be reassessed with repeat PFTs and HRCT post-treatment.Most patients put on this treatment regimen have been found to exhibit clinical improvement and stability.39However, prognosis is poor in patients whose condition worsens further, and lung transplants may be considered in patients with advanced disease (DLco < 40% predicted) or progressive (≥ 10% decline in FVC or ≥ 15% decline in FVC within 6 months of follow-up).Generally, patients over the age of 65 years and/or those with significant comorbidities are excluded from this criterion.23,39

Figure 4 .
Figure 4. Algorithm of the proposed therapeutic approach to patients with RA-ILD (Adapted from White et al 28)

Table 1 : Criteria for diagnosis of methotrexate-pneumonitis by Searles and McKendry 22
Table 1 lists the criteria for diagnosis methotrexate pneumonitis.