Question
What are the treatment options for rheumatoid fibrosing alveolitis?

Response from Robert I. Fox, MD, PhD Professor/Member, Scripps Memorial Hospital and Research Foundation; Rheumatologist, Scripps Memorial Hospital, LaJolla, California

Response

Optimal therapy for fibrosing alveolitis (part of the spectrum of interstitial lung disease [ILD]) has not been clearly established. To date, most treatment strategies have been based on eliminating or suppressing the inflammatory component. No pharmacologic therapy has been shown to unequivocally alter or reverse the inflammatory process of idiopathic pulmonary fibrosis (IPF). It has been suggested that ILD in association with rheumatoid arthritis (RA) is less severe or progressive than idiopathic ILD.

Comment

Corticosteroid therapy produces variable subjective and objective improvement in the treatment of rheumatoid arthritis interstitial lung disease (RA-ILD); as with other forms of idiopathic ILD, the results may depend upon the extent of inflammatory or fibrotic changes within the pulmonary parenchyma.

At our clinic, we recommend initiating therapy with oral prednisolone at a dose of 0.5 mg/kg per day (based on ideal body weight) as a single-morning dose. A maximum dose of 100 mg/day should not be exceeded. If a response is going to occur, it is usually seen within 1-3 months. The prednisolone dose should be slowly reduced to a maintenance dose of 10 mg/day once a response occurs, using pulmonary function tests to monitor disease activity.

The treatment of IPF has been based on the concept that inflammation leads to injury and fibrosis. Initially, it was hypothesized that inflammatory and immune effector cells accumulate within the pulmonary parenchyma. As this alveolar and interstitial reaction is perpetuated, alveolar-wall, vascular, and airway damage ensues; reparative processes are inadequate or impaired; and fibrosis develops. Eventually, the lung parenchyma is irreversibly deranged and gas exchange function impaired. When the ventilatory reserve is sufficiently diminished, symptoms of respiratory insufficiency become apparent.

Although this conceptualization of the pathologic process suggests numerous theoretical points for therapeutic intervention, the practical treatment armamentarium has been largely restricted to anti-inflammatory medications and, most recently, lung transplantation.

Drugs reported to be beneficial include cyclophosphamide, mycophenolic acid, methotrexate, azathioprine, hydroxychloroquine, d-penicillamine, and cyclosporine. If a patient fails to respond or deteriorates during the initial trial of corticosteroids alone, addition of an immunosuppressive drug should be considered. Therefore, an alternative initial regimen includes prednisolone (20 mg/day) plus either azathioprine (3 mg/kg orally up to 200 mg/day) or cyclophosphamide (100-120 mg orally/day as a single daily dose). Alternatively, cyclophosphamide may be administered by monthly intravenous pulse therapy.

Other antifibrotic agents are being tested in the treatment of lung fibrosis and include interferon gamma, interferon beta, relaxin (increases procollagenase), pirfenidone, halofuginone (inhibits collagen synthesis), suramin (profibrotic cytokine inhibition), and prostaglandin E2 (inhibits collagen production).

Because epithelial injury in IPF may be mediated by oxygen radicals, it has been suggested that antioxidant strategies might prove beneficial. Possible strategies might include delivery of antioxidant enzymes to the lung parenchyma or even promoting increased genetic expression of antioxidant enzymes. Glutathione (an effective scavenger of toxic oxidants that suppresses lung fibroblast proliferation in response to mitogens), taurine (a natural free amino acid), and niacin inhibit the development of experimental fibrosis (better than either agent alone) in an animal model. High-dose N-acetylcysteine, as a glutathione precursor, has been suggested as an adjunct to maintenance immunosuppression therapy in patients with IPF.

Another potential strategy would be to interfere with the process of leukocyte retention in the lung. Leukocyte adhesion molecules play an important role in this process. Antibodies to such adhesion molecules have been shown to prevent collagen deposition in an animal model of lung injury. Agents that block the expression or function of adhesion molecules are rapidly becoming available and may someday prove clinically useful.

Single lung transplantation may be an option in end-stage RA-ILD, although, compared with IPF, it is less likely to be required because the RA-ILD follows a more benign course. There are no studies reporting the outcome of lung transplantation for end-stage RA-ILD. Side effects of the therapy for RA (eg, osteoporosis) may be a contraindication, and extrapulmonary and extra-articular disease activity may complicate transplantation.

The impact of newer therapies for RA (eg, anti-TNF regimens) that decrease inflammation and may interfere with fibrosis are awaited with interest.