Special Feature

Immunology and Cell Biology (2003) 81, 350–353; doi:10.1046/j.1440-1711.2003.01184.x

Past, present and future drug treatment for rheumatoid arthritis and systemic lupus erythematosus

Patricia L Mottram1

1Helen Macpherson-Smith Trust Inflammatory Diseases Laboratory, Austin Research Institute, Kronheimer Building, Austin and Repatriation Medical Centre, Melbourne, Victoria, Australia

Correspondence: Dr Patricia L Mottram, Austin Research Institute, Kronheimer Building, A & RMC, Studley Road, Heidelberg, Vic. 3084, Australia. Email: p.mottram@ari.unimelb.edu.au

Received 16 June 2003; Accepted 17 June 2003.

Top

Abstract

Historically, treatment of complex autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus has aimed to relieve symptoms, and in severe cases, use broad-spectrum immunosuppressive treatments in attempts to induce permanent remission. Recent research into the causes of chronic autoimmune inflammatory activation have not only explored the mechanism of action of known therapies, but also provided a number of new targets for therapy, by identifying the cells, cytokines and signalling pathways activated during autoimmune antibody mediated processes. This review briefly outlines progress in the understanding of the autoimmune nature of rheumatoid diseases and the expansion of treatment options, from broad to specific immunotherapies for these closely related diseases.

Keywords:

autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, treatments

Top

Introduction

Of the more than 100 known rheumatoid diseases and syndromes, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are the most common. These diseases are autoimmune systemic conditions affecting joints and other many organs (e.g. kidney in SLE) and are characterized by chronic inflammation initiated by deposition of auto-antibodies and immune complexes in the target organs. Rheumatoid arthritis and SLE have common immune mechanisms, characterized by inflammatory processes, including T cell activation, providing B cell help for auto-antibody production, infiltration of organs by inflammatory cells (macrophages, neutrophils) and the chronic secretion of inflammatory cytokines (TNF-alpha, IL-1, IFN-gamma, IL-6) that can lead to tissue enzyme activation (e.g. collagenase in synovial tissue) and organ destruction. Effective treatments range from transient alleviation of symptoms, to prevention of organ damage and immune modulation to eradicate or inhibit the autoimmune responses. It is interesting to note that the oldest therapies, salicylates, quinine and gold, are still used today, often in combination with newer treatments. Also, antibiotics, used on the mistaken premise that rheumatoid diseases were caused by persistent infectious agents, have proved useful because of their effects on immune processes.

The diversity of therapeutic approaches has increased dramatically in the last 20 years, with a wide range of options now offering greater chances of finding effective treatment for individual patients. However, most treatments still have undesirable side-effects and none can promise permanent disease remission. There is still much work to be done to alleviate the suffering caused by these debilitating chronic diseases. A very useful, comprehensive list of current treatments, side-effects and drug interactions is available from the Arthritis Foundation USA website1. Some of these are included in Table 1.


Top

Medicines, ancient and modern

Willow bark: The origins of non-steroidal anti-inflammatory drugs

The earliest treatments for rheumatoid disease were probably concoctions containing willow or poplar bark, both being sources of salicylin. Herbal remedies such as these were recorded in ancient Egyptian and Roman times2. The active ingredient, acetylsalicylate, was isolated in 1829 and first used medically as aspirin in 18993. Aspirin and its related compounds, designated as non-steroidal anti-inflammatory drugs (NSAID) have been, and are still, the mainstays of treatment to provide symptomatic relief for chronic inflammatory diseases such as SLE and RA.

These drugs block inflammation by inhibition of prostaglandin release. All cells in the body respond to tissue damage by secreting prostaglandins. In this process, arachidonic acid is oxidized and cyclized by cyclooxygenase enzyme (COX). There are two isoforms: COX-1 and -2. Aspirin and its relatives (more than 20 related drugs) inhibit the activity of both forms of the enzyme, while newer drugs, such as Celebrex, inhibit only COX-2, avoiding some of the gastrointestinal side-effects of aspirin (COX-1 is required for the production of protective prostaglandins in the digestive tract)4.

Peruvian cinchona tree bark: Antimalarials

Infusions of the bark of the Peruvian cinchona tree have been used for centuries for medicinal purposes and were observed to have both antimalarial and anti-inflammatory properties. The active agents, quinine and cinchonine were isolated and used as early as 1894 to treat lupus5. As slow acting, low toxicity drugs they are useful in combination therapy, especially for SLE, since their mode of action is quite different to other anti-inflammatory drugs. They act by inhibiting lysosomal and endosomal function, thus limiting the release of secreted proteins, including cytokines. Antigen processing and presentation, and thus T cell activation are also inhibited6.

Combating infection: Antibiotics

The use of antibiotics to treat RA began in the 1930s with the belief that the usual causative agent was infectious. While it is true that infections can cause transient arthritis and may trigger autoimmune disease7, infectious agents are not commonly found in RA or SLE patients. However, treatment with sulphur drugs in the 1930s was effective, possibly because the original treatment preparations, from Pharmacia in Sweden, contained covalently linked salicylic acid (aspirin) with an antibacterial sulfapyridine, providing an early form of combination therapy8. It can occasionally induce lupus in RA patients, so is not presently used in SLE treatment. Mechanisms of action include those of NSAID, with added inhibition of antibody secretion. The treatment fell out of favour when the autoimmune nature of rheumatoid disease was discovered, but has been used recently in combination with other treatments9.

Tetracycline therapy for RA was also used on the premise that RA was caused by infectious agents. Originally used in the 1950s, the anti-inflammatory properties of tetracyclines and related drugs such as Doxycycline and Minocycline have been demonstrated to be separate from their antibacterial actions. They can inhibit collagenase activity, chemotaxis and phagocytosis of neutophils. Inhibition of T cell activation regulates inflammatory mediators and cytokines such as TNF-alpha and IFN-gamma10. Tetracyclines are, like many RA and SLE treatments, not effective in all patients. There is a wide spectrum of responses, possibly linked to HLA expression11. Although adverse side-effects are rare, autoimmune hepatitis and SLE have been reported12.

Disease modifying anti-arthritic drugs, gold and tuberculosis

Disease modifying anti-arthritic drugs (DMARD) are agents that change immune responses long-term, more dramatically than NSAID, and provide some chance of permanent remission. This group includes many cytotoxic drugs that reduce immune function, by decreasing bone marrow function, thus acting as powerful anti-inflammatory agents. Immune suppression is a side-effect (with increased infection and cancer risk). The earliest forms of DMARD were gold salts and colloidal gold, originally used in the treatment of tuberculosis and in RA in the 1920s, again based on the hypothesis that RA was caused by a tuberculosis infection13. These preparations are still used in the treatment of rheumatoid disease. Although the mechanism of action is largely unknown, gold compounds have been observed to decrease cellular proliferation, reduce antibody and cytokine release and inhibit collagenase action. Side-effects, however, can include decreased renal function, acute pulmonary distress and decreased liver function with long-term treatment. This very expensive treatment declined in popularity with the use of alternative DMARD in the 1980s14.

Since the 1950s, cytotoxic drugs with powerful immunosuppressive effects that were developed for cancer therapy have been adapted for use in rheumatoid diseases. These include the alkylating agents, that cross link DNA, impairing cell division and purine analogues such as Azathioprine that decrease the circulating lymphocyte count, thus eliminating many inflammatory cells. Other immunosuppressive drugs developed to combat organ transplant rejection (Cyclosporine, Tacrolimus and Sirolimus) selectively impair T cell activation and IL-2 secretion. Thalidomide inhibits angiogenesis and TNF-alpha production. All of these drugs have potentially life threatening side-effects, due to severe depression of immune function, but offer the best chance at present of inducing permanent remission of disease15.

The folic acid antagonist Methotrexate has a different mechanism of action, but was also developed in the 1950s as a cancer therapy. Although high doses are immunosuppressive and only used in severe rheumatoid disease, low dose therapy has proved highly effective for the treatment of RA and SLE16. Low dose therapy avoids suppression of T cell activities, but still inhibits humoral immunity, decreasing the serum immunoglobulin levels and cytokine secretion by the induction of apoptosis of infiltrating cells in the synovium17. Reduced inflammatory cytokines, particularly IL-1, IL-6 IL-19 and TNF-alpha, were seen after treatment, while increases in IL-10 and IL-4 promoted Th2 cytokine effects that may be protective against autoimmune disease18. Methotrexate is particularly effective in combination with other anti-inflammatory drugs9.

Hormones

Glucocorticoids revolutionized the treatment of inflammation when first used for the treatment of RA by Hench in 194919. These steroid hormones, like NSAID, inhibit prostaglandin synthesis, but at an earlier step in the pathway, prior to arachidonic acid synthesis. They also block cytokine secretion and T cell activation, and inhibit COX-2 activity. These drugs (Cortisone, Dexamethasone, Prednisolone, Prednisone) are still commonly used to treat RA and are the standard treatment for SLE. Long-term, high dose treatment is now avoided by combining these agents with other treatments. Since these agents bind to almost all cells in the body, they have profound effects on physiological systems. If used in long-term therapy they can cause profound immunosuppression, with an increased risk of cancer and infection, osteoporosis, gastrointestinal ulceration, hypertension and endocrine abnormalities20.

Biological agents

Due to better understanding of immune mechanisms, and advances in biotechnology allowing antibody engineering, new agents, typically monoclonal antibodies, are now available for specific blockade of inflammatory mediators without causing general immunosuppression. To date more than 20 mAbs have been approved for clinical use by the US Food and Drug Administration (FDA) and many others are in clinical trials. Current targets for biologic reagents undergoing trials include: (1) adhesion molecules, chemokines and complement regulators involved in inflammatory cell infiltration (ICAM-1, CD11a, IL-8, C5); (2) T cell surface interactive molecules (CD4, CTLA4-Ig, CD40L, MHC peptides), and (3) inflammatory cytokines (TNF-alpha, IL-1, IL-6). The latter, including FDA licensed Adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), all inhibiting TNF-alpha, have proved useful in treating RA. The newest mAb, anakinra (Kineret), approved just a year ago, blocks the action of the cytokine IL-11.

The advantages of treatment with biological agents include their rapid action and reversible effects when treatment is withdrawn, thus minimizing debilitating side-effects. Their specificity of action makes them highly compatible with other treatments, including DMARD. Problems in their use include the need for intravenous administration, their immunogenicity that may limit repeat treatments and the high cost of manufacture and hence, of treatment. Long-term treatment with biological agents, with and without other drugs, is as yet in the early stages. With further research, clinical follow-up and identification of new molecular and cellular targets, we may be able to induce immune deviation or to re-establish tolerance to autoantigens, and thus ensure complete remission of disease21, 22.

With new data from X-ray crystallography, strategies other than the production of biological agents are also available for the development of new treatments. Recent findings have shown that Fc receptors are a potential target for immunotherapy, given their central role in immune complex mediated disease23. Based on crystallization and structural analysis24, 25, of the most widely expressed, uniquely dimeric, human FcRgammaIIa, rational drug design can be used to produce small chemical entities likely to inhibit receptor function26. The solved 3D structures of not only FcRgammaIIa, but also hFcRgammaIII/IgG and hFcRgammaI/IgE complexes provide great opportunities to design and test new anti-inflammatory agents that will add to the present spectrum of treatments available for these very complex diseases.

In reviewing the history of rheumatoid disease treatment, it was interesting to note how many of the old treatments are still in use, although often in modified, purified or improved form. Modern versions of willow and Peruvian cinchona bark (Aspirin and Chloroquine, respectively) are good examples of ancient remedies still in use. Other agents, such as antibiotics and gold salts, were tested as remedies based on a false premise, that rheumatoid disease was due to persistent infection rather than autoimmunity, but they have been proven to be useful due to other mechanisms of action. Reagents developed as immunosuppressants for transplantation or cytotoxics and antimetabolites for cancer therapy have been subsequently used to great effect in the treatment of the inflammation induced by immune complexes. It is only recently, with our greater understanding of the molecular and cellular processes of chronic inflammation, that biological reagents such as anti-TNF-alpha and IL-1 mAbs have been developed and trialled specifically for the treatment of rheumatoid diseases. Solving the structures of key participants in the inflammatory process, such as FcR, will allow further exploration and specific drug design to refine and improve the effectiveness of anti-inflammatory therapy for RA, SLE and related diseases. Given the long clinical lifespan of known anti-inflammatory treatments and continuing exploration of their mechanisms of action, no doubt they will continue to be used along with new agents.

Top

References

  1. Arthritis Foundation. 2003; Available from URL: http://www.arthritis.org
  2. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am. J. Med. 1998; 104: 2S–8S; discussion 21S–2S. | Article | PubMed | ChemPort |
  3. Rodnan GP, Benedek TG. The early history of antirheumatic drugs. Arthritis Rheum. 1970; 13: 145–65. | PubMed | ChemPort |
  4. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 1998; 38: 97–120. | Article | PubMed | ISI | ChemPort |
  5. Pap T, van der Laan WH, Aupperle KR et al. Modulation of fibroblast-mediated cartilage degradation by articular chondrocytes in rheumatoid arthritis. Arthritis Rheum. 2000; 43: 2531–6. | Article | PubMed | ChemPort |
  6. Fox RI, Kang HI. Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation. Lupus 1993; 2: S9–S12. | PubMed | ChemPort |
  7. Ruddy S, Harris E, Sledge B eds. Arthritis related to infection. In: Kelley's Textbook of Rheumatology, Vol. 2 6th edn. Philadelphia, USA: WB Saunders, 2001; 1469–539.
  8. Svartz N. Salazopyrin, a new sulfanilamide preparation. Acta. Med. Scand. 1942; 110: 577–9.
  9. O'Dell JR, Haire CE, Erikson N et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N. Engl. J. Med. 1996; 334: 1287–91. | Article | PubMed | ChemPort |
  10. O'Dell JR, Haire CE, Palmer W et al. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1997; 40: 842–8. | PubMed | ChemPort |
  11. Reveille JD, Alarcon GS, Fowler SE et al. HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline Rheumatoid Arthritis. Arthritis Rheum. 1996; 39: 1802–7. | PubMed | ChemPort |
  12. Angulo JM, Sigal LH, Espinoza LR. Coexistent minocycline-induced systemic lupus erythematosus and autoimmune hepatitis. Semin. Arthritis Rheum. 1998; 28: 187–92. | Article | PubMed | ChemPort |
  13. Forestier J. Rheumatoid arthritis and its treatment by gold salts. J. Lab. Med. 1935; 20: 827–30.
  14. Ward JR, Williams HJ, Egger MJ et al. Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 1983; 26: 1303–15. | PubMed | ChemPort |
  15. Stein M. Immunoregulatory drugs. In: Ruddy S, Harris E, Sledge E, (eds) Kelley's Textbook of Rheumatology, Vol. 1 6th edn, Philadelphia, USA: WB Saunders, 2001; 879–98.
  16. O'Dell JR, Haire C, Erikson N et al. Efficacy of triple DMARD therapy in patients with RA with suboptimal response to methotrexate. J. Rheumatol. 1996; 44 (Suppl): 72–4. | ChemPort |
  17. Nakazawa F, Matsuno H, Yudoh K et al. Methotrexate inhibits rheumatoid synovitis by inducing apoptosis. J. Rheumatol. 2001; 28: 1800–8. | PubMed | ISI | ChemPort |
  18. Barrera P, Boerbooms AM, Janssen EM et al. Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor alpha, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy. Arthritis Rheum. 1993; 36: 1070–9. | PubMed | ChemPort |
  19. Hench P. The reversibility of certain rheumatic and non-rheumatic conditions by the use of cortisone or of the pituitary adenocorticotropic hormone. Ann. Intern. Med. 1952; 39: 1818–27.
  20. Pincus T, Callahan LF. What is the natural history of rheumatoid arthritis? Rheum. Dis. Clin. North Am. 1993; 19: 123–51. | PubMed | ChemPort |
  21. Walker MG. Z39Ig is co-expressed with activated macrophage genes. Biochim. Biophys. Acta. 2002; 1574: 387–90. | PubMed | ISI | ChemPort |
  22. Haraoui B, Strand V, Keystone E. Biologic agents in the treatment of rheumatoid arthritis. Curr. Pharm. Biotechnol. 2000; 1: 217–33. | Article | PubMed | ChemPort |
  23. Hogarth PM. Fc receptors are major mediators of antibody based inflammation in autoimmunity. Curr. Opin. Immunol. 2002; 14: 798–802. | Article | PubMed | ISI | ChemPort |
  24. Maxwell KF, Powell MS, Hulett MD et al. Crystal structure of the human leukocyte Fc receptor, Fc gammaRIIa. Nat. Struct. Biol. 1999; 6: 437–42. | Article | PubMed | ISI | ChemPort |
  25. Powell MS, Barton PA, Emmanouilidis D et al. Biochemical analysis and crystallisation of Fc gamma RIIa, the low affinity receptor for IgG. Immunol. Lett. 1999; 68: 17–23. | Article | PubMed | ChemPort |
  26. Pietersz GA, Powell M, Ramsland PA, Hogarth PM. Fc receptor structure and the design of anti-inflammatories. New therapeutics for autoimmune disease. Annu. Reports Med. Chem. 2002; 37: 217–24. | ChemPort |