Despite increasing use of several potent immunosuppressive or cytotoxic agents for benign pulmonary disorders, their role has not been clearly defined in randomized controlled studies. Further, the mechanisms by which individual agents confer benefit in autoimmune disorders are poorly understood. Interpretation of efficacy is complicated by the pronounced variation in immunosuppressive effects of individual drugs, depending on the dose, route of administration, duration of administration, and underlying disease(s). Randomized controlled clinical trials are critical to determine the efficacy of therapeutic regimens, but several factors cloud interpretation. The course of many inflammatory pulmonary disorders is highly variable; interpretation of therapeutic interventions may be difficult to distinguish from the natural history of the disease. For all of the inflammatory pulmonary disorders, corticosteroids are considered a critical component of therapy. Since immunosuppressive agents may act synergistically with corticosteroids, trials using differing doses of corticosteroid (or no corticosteroids) may achieve disparate results. The timing of administration is a critical determinant of outcome. Immunosuppressive or cytotoxic agents are often added late in the course of diseases when irreversible damage has already occurred. In this context, failures are inevitable. In future clinical trials, the most accurate techniques to discriminate reversible from irreversible disease are essential. In the context of chronic interstitial lung disorders, this may entail use of surrogate markers of alveolitis such as HRCT or BAL even though the clinical application of these techniques is highly controversial. Delay in initiation of cytotoxic therapy until obvious failure of corticosteroids has occurred may preclude favorable effects of therapeutic regimens that might have been effective earlier in the course of the disease(s). Although the limitations of existing data have been emphasized in this review, most experts consider daily oral CTX to be the most potent, but also most toxic, immunosuppressive agent currently available. Substituting monthly pulse CTX for oral CTX may reduce toxicity but may alter efficacy. Methotrexate and azathioprine have primarily been used as corticosteroid-sparing agents, but additional indications include their use as substitutes for CTX in patients experiencing or at risk for CTX adverse effects and as initial (primary) therapy for nonfulminant diseases traditionally treated with CTX. Their roles need to be more crisply defined in randomized controlled trials comparing these less toxic immunosuppressive drugs with oral CTX. Due to its potential for late sequelae (e.g., cirrhosis), MTX is less attractive than azathioprine for chronic inflammatory disorders requiring prolonged therapy (years). However, direct comparisons between these agents need to be done to clarify their respective roles. Cyclosporin A has a limited role for pulmonary disorders because its effects are not sustained and adverse effects with long-term use are nearly ubiquitous. Combinations of immunosuppressive agents have been used for some autoimmune disorders and may sometimes enhance efficacy, but this is not uniform. In a randomized placebo-controlled double-blind trial, the combination of cyclosporine plus MTX was superior to MTX alone in patients with severe RA. In contrast, a randomized multicenter trial found that the combination of azathioprine plus MTX was no more effective than MTX alone in ameliorating radiographic progression in patients with RA. Scientific studies investigating multi-agent regimens are best performed in diseases in which therapy with individual immunosuppressive agents has been well studied in controlled trials. Unfortunately, for most pulmonary disorders that are currently with immunosuppressive or cytotoxic agents, controlled randomized trials are sparse or lacking. Trials of combination therapies in this context may be tried as a last resort but are unlikely to answer substantive issues regarding efficacies. Immunomodulatory agents such as gold, sulfasalazine, intravenous immunoglobulin, colchicine, D-penicillamine, tacrolimus (FK506), or mycophenolate have been considered, either singly or in combination, as therapy for inflammatory pulmonary disorders, but data are lacking. Space constraints do not allow further discussion of these immunomodulatory agents here. Hydroxychloroquine has been used as therapy for sarcoidosis and asthma in uncontrolled trials and in randomized controlled trials for RA, systemic lupus erythematosus, and other autoimmune disorders. The combination of hydroxychloroquine with MTX and sulfasalazine was more effective than MTX alone or sulfasalazine plus hydroxychloroquine in randomized double-blind trial of 102 patients with RA.
