Targets for New SLE Treatments

A remarkable meeting, SLE: Targets for New Therapeutics, took place at the National Institutes of Health (NIH) in Bethesda, MD, January 10-12, 2002. The meeting brought together world leaders in the contemporary biology of lupus to focus on specific targets that may be amenable to treatment interventions. It also presented a unique private-public sector collaboration that, unequivocally, will improve the lot of lupus patients. Attendees included scientists, clinicians, and people from the biopharmaceutical world. (This report provides a non-technical overview of the meeting. A more detailed technical review will be available later at this site.)

The meeting was organized by:

• Jane Salmon, MD, Hospital for Special Surgery/Weill-Cornell (HSS);
• David Wofsy, MD, University of California, San Francisco (UCSF);
• Margaret G. Dowd, S.L.E. Foundation, Inc.;
• Susana Serrate-Sztein, MD, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH; and
• Elizabeth Gretz, PhD, NIAMS.

Sponsors were: S.L.E. Foundation, Inc.; NIAMS; Lupus Research Institute; Office of Research on Women's Health, NIH; National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], NIH; and the National Institute of Allergy and Infectious Diseases, NIH. Merck & Co., Inc., provided additional financial support.

The meeting was organized to cover the following topics:

1. Essential Causes (etiology);
2. Susceptibility to lupus;
3. How lupus progresses (pathogenesis);
4. How lupus damages the body (tissue injury);
5. What treatments are available/can be developed to attack lupus at each of the above points.

The participants at the meeting did not attempt to prioritize the targets they identified. (Surely others will do so later.) An important and innovative evening session tried to identify problems and possibilities in clinical trials in SLE. Individual experts gave their wish lists for conducting such trials; audience members, including patients, debated the practicalities.

Essential Causes (Etiology)

The cause of lupus is not known. Anti-DNA antibody and a very-high female/male ratio are essential characteristics of the disease and clues to its origins. The speakers in this section of the meeting offered arguments for the following possible causes of SLE: a common virus, such as the Epstein-Barr (mononucleosis) virus;[1] bacteria, with bacterial DNA being the inciting cause of anti-DNA antibody;[2]a variety of factors related to the unusual sex ratio of lupus[3] (9 women to 1 man); naturally occurring cell death as a source of the DNA that induces anti-DNA antibody;[4] and exogenous chemicals, such as a component of mineral oil.[5] The speakers used mouse models and human experience to support their positions.

Underlying Susceptibility to Lupus

The leading contemporary theory of lupus etiology argues that the inciting cause of lupus is something very common in human experience (such as mononucleosis), but that the patient is in some way unusually susceptible to becoming ill. That is, people develop lupus because they cannot handle the cause, whatever it may be, in a normal way. The cause "triggers" some underlying susceptibility

The vast amount of data coming from the study of human and mouse genes strongly suggests that "susceptibility genes" will be found. This portion of the program featured speakers who study mouse lupus genes;[6][7] and human lupus genes.[8][9][10][11] Mark Walport[12] described his imaginative hypothesis that lupus is a disease in which the normal 'garbage' of cell functions cannot be disposed of properly. He suggested that subtle genetic defects interfere with disposal mechanisms. The geneticists of mice and men presented evidence for susceptibility genes, but without general agreement except for this: (1) susceptibility, when it is ultimately defined, will be due to many genes, not just a few, (2) genes determine which organs will be affected, and how severely, and (3) human race (and mouse strain) is very important.

How Lupus Progresses (Pathogenesis)

The immune system is very complex. An immune reaction starts when a cell performing a type of surveillance function encounters something it doesn't like. Then the surveillance cell has to move forward to attack the invader and to tell an immune cell to turn itself on. The immune cell has to recognize the attack cell's message, turn on, recruit other cells, and (either itself or other cells) create chemicals to kill the invader. Still other cells then have to finish the killing and dispose of the invader's corpse. However, the immune cell can also conclude that the attack cell's message is false and that it need not turn itself on. Finally, other cells and systems have to be in place to turn the entire process off.

The section of the meeting on pathogenesis considered some of the many ways that these functions go awry in SLE. Some speakers addressed the question of how the immune system controls itself (immunoregulation).[13][14] Joseph Craft[15] considered how an immune cell decides to turn on or stay quiet (tolerance). One speaker discussed how messages are transmitted,[16] and two others[17] talked about the process of immune cells turning on and staying turned on. All of these processes have complicated technical names. A very large number of processes are critical to the development of a normal (or abnormal) immune response. Each process suggests a way in which it can be changed to make an ill person better. Of all the topics considered at this meeting, these control processes (immunoregulation) offer the best possible therapeutic targets.

How Lupus Damages the Body (Tissue Injury)

Turning on the immune system is one issue, but a person does not become ill unless the immune system successfully recruits the cells that can do damage, and unless the damage-causing cells actually do cause injury. Whether the damage-causing cells have run wild, or whether they are simply obeying an evil commander, if they can be controlled the patient will not become ill.

Speakers in this part of the meeting offered the most novel ideas for breaking the back of lupus. Jane Salmon[18] showed how the complement system (a series of proteins that the immune system calls into play) unexpectedly is also critical in the blood clotting system - which itself is a cause of damage in lupus. A hematologist approached the problem from the other side, showing how the clotting system and inflammation are inextricably intertwined;[19] another, also from the field of blood clotting, discussed how cells maintain their integrity and attach to one another, and how these processes might work badly to cause diseases like lupus.[20] Betty Diamond[21] offered a surprising new insight on how an anti-DNA antibody can attack a part of the brain that does not contain DNA. Two additional speakers had special insights how genetic abnormalities affecting cells that damage tissues can cause clinical illness similar to what we recognize as lupus.[22][23]

Potential New Treatments

The final session began with David Wofsy's[24] review of the very large number of potential therapeutic targets that the preceding discussions identified. The table below (incompletely) lists the technical names of these targets according to the parts of the immune system they affect.

System	Target
T-cell	Anti-CD3
	Anti-CD4
	Anti-CD40L
	CTLA4-Ig
B-cell	Anti-CD20
	Anti-CD22
	Anti-B7
	TAC-Ig
	LJP 394
Cytokine	Anti-INFg
	Anti-IL10
	Anti-IL6r
Complement	Anti-C5
Regulatory cell	CD4+ CD25+ T-cells
Stem cell	Transplantation

This session reviewed the current status of cytotoxic drug therapy, concluding that cyclophosphamide (Cytoxan) remains the most effective drug, but noting that new treatment regimens may reduce its toxicity[25] (side effects). In mice, a biologic agent coupled with a very short course of cyclophosphamide combine to produce a response far better than either alone.[26] B cells themselves can be targeted,[27] and the complement system can be inhibited.[28] Finally, Michelle Petri reviewed her experience with immunoablation with high dose cyclophosphamide,[29] and Ann Traynor presented an experience with immunoablation with stem cell replacement.[30]

Treating the Whole Patient

Both a strength and a weakness of the meeting was its focus on highly specific, usually immunologic, molecular targets amenable to intervention in patients with SLE. Except for a highly innovative evening plenary session, the meeting spent very little time on the concept of the whole patient, or on short-term versus long-term issues of treatment.

The special session, entitled Drug Trials and Tribulations, asked a panel of investigators from government, academia, the biotechnology industry,[31][32][33][34][35] and a patient to discuss what does and does not work in constructing drug trials for patients with SLE. Audience members were invited to participate. Overall, the concept of multiple organ system involvement, small numbers of patients, the non-concordance of disease activity measures, and the lack of suitable instruments to measure responses to treatment were again identified. The Food and Drug Administration (FDA) is preparing a guidance document to assist this measurement.[36] What's Next?

An American College of Rheumatology workshop, convened by Matthew Liang,[37] to be held in Dusseldorf, Germany, in May 2002, may be able to provide a solution. An important future problem to address will be short-term (controlling inflammation) versus long-term (controlling damage) goals of treatment. Another will be the intermittency of SLE. A third will be the need to decide, for treatment trials, whether lupus should be considered as one disease or multiple separate diseases (arthritis, rash, nephritis, vasculitis, clotting, brain disease). If these problems are solved, then the targets identified in this meeting can be rationally put into play.