Systemic Lupus Erythematosus and Sjogren Syndrome
Systemic Lupus Erythematosus and Sjogren Syndrome
The science of lupus has advanced dramatically. The articles presented in this volume of Current Opinion in Rheumatology promise innovative treatments for systemic lupus erythematosus (SLE). Are these expectations realistic?
Could inhibition of complement limit tissue damage? Could enhanced availability of complement optimize clearance of apoptotic material and limit breaks in tolerance? The review by Hector Molina, MD, addresses these questions.
Can we inhibit mediators of tissue damage in the kidney or the vasculature to prevent irreversible damage? If we understand mechanisms of injury, we are more likely to identify targets for treatment. The review by Jim C. Oates, MD, and Gary S. Gilkeson, MD, and the reveiw by Joan T. Merrill, MD, describe mediators of renal and vascular disease, respectively.
Precise characterization of disease phenotype is essential for testing therapies. Melanie J. Harrison, MD, MS, and Lisa D. Ravdin, PhD, discuss this issue with relation to central nervous system SLE. Finally, some new agents already in trials are described by Bryan D. Gescuk, MD, PhD, and John C. Davis, Jr., MD, MPH, MS, and William Stohl, MD, PhD.
Recent discoveries in genetics, molecular and cell biology, immunology, and etiology, reviewed at the SLE: Targets for New Therapeutics conference held at the National Institutes of Health, Bethesda, MD, in January 2002, have advanced optimism that a cure for lupus is within reach. The speakers at this NIH conference and scientists funded by various voluntary agencies have identified "targets" to aim for, to effect a lupus cure. What are these targets? Recent work has focused on identifying biologic molecules critical to the lupus disease process and on strategies to remove or neutralize them. Many such targets are known ( Table 1); most function as immune recognition sites or effectors. It is hoped that recognition of the critical target will allow development of a pharmacologic or biologic agent: "the cure."
However, lupus has a way of confounding experts. Like "target," "cure" has not been fully defined. Just 4 months after the NIH conference, a group of researchers sponsored by the American College of Rheumatology and co-sponsored by several groups and agencies, convened in Düsseldorf Germany, and found it difficult (but not impossible) to agree, even on measurement criteria for lupus response. Is cure the same as disease prevention? Is it amelioration or remission of established illness? Or is cure prevention or reversal of disease-caused complications?
To complicate the issue further, many events precede clinical recognition of disease (Fig. 1). Factors that influence the vulnerability to, and the course of lupus-perhaps the critical targets-and precede the diagnosis of disease include (genetic) susceptibility, a triggering agent, an incubation period (perhaps host or agent maturation or a requirement for a second trigger), and a phase of subclinical, incomplete, or undiagnosable disease (seropositivity in patients without clinical findings, or forme fruste, evolving and overlap syndromes). Factors that follow diagnosis include symptom recognition and documentation, subclinical damage (atherosclerosis, thrombosis, renal failure, osteoporosis, osteonecrosis, cognitive dysfunction), and development of symptoms related to damage. The search for a single target assumes the persistence and relevance of that target at each stage. Lupus is chronic, relapsing, and polymorphic. There may be several targets, and different targets in different phases of disease.
(Enlarge Image)
Relationships among potential targets in systemic lupus erythematosus. Years may evolve between exposure to a trigger agent and clinical symptoms. Note also that damage caused by disease or treatment of one organ system, eg, hypertension due to steroid treatment of nephritis, may lead to damage of another organ system, eg, cognitive dysfunction, independent of active systemic lupus erythematosus. Note also that organ systems may become involved independently and at different times. Identifying a single target for damage accrual of a single organ may give misleading information.
Disease activity in one organ system may not parallel disease activity in another system. For instance, thrombocytopenia and arthritis often develop and advance independently, as do renal and neurologic symptoms. It is also not evident that disease in different organ systems will have identical therapeutic targets, even when such disease activity is simultaneous. Because lupus evolves over years, short-term proxies for long-term response will be necessary; but, as yet, no validated proxies for outcomes exist. Whether an index of total disease activity is a more useful guide for clinical studies than measures of individual organ systems remains unclear. After much debate, the Düsseldorf group preferred organ-specific to global indices.
Thus, it is doubtful that the discovery of a single target, leading to a single cure, is either imminent or realistic over the long term. However, even if an all-encompassing cure is not "just around the corner," the future is quite bright. With remarkable progress in our understanding of how the immune system works, how genes modulate disease, and how to manufacture molecules that perform highly specific tasks, it is inevitable that the critical targets will be identified and lupus will continue to yield to our efforts. The challenge is to choose wisely among potential targets as the basic scientists expose more molecules relevant to disease, to ask clearly defined questions, and to develop an infrastructure for clinical investigation so that these questions can be answered. For some years, clinical investigation of lupus in the United States has been uncoordinated. The recent series of meetings offers a new consensus and a fresh start. With outcome measurement criteria in place and validated outcome proxies expected in the near future, we are poised to translate progress made at the molecular level into innovative tests and treatments for patients afflicted with lupus. We call on all physicians who care for lupus patients, and on the agencies-both government and private-charged with funding lupus research, to join in this task.
Abbreviations:SLE systemic lupus erythematosus
The science of lupus has advanced dramatically. The articles presented in this volume of Current Opinion in Rheumatology promise innovative treatments for systemic lupus erythematosus (SLE). Are these expectations realistic?
Could inhibition of complement limit tissue damage? Could enhanced availability of complement optimize clearance of apoptotic material and limit breaks in tolerance? The review by Hector Molina, MD, addresses these questions.
Can we inhibit mediators of tissue damage in the kidney or the vasculature to prevent irreversible damage? If we understand mechanisms of injury, we are more likely to identify targets for treatment. The review by Jim C. Oates, MD, and Gary S. Gilkeson, MD, and the reveiw by Joan T. Merrill, MD, describe mediators of renal and vascular disease, respectively.
Precise characterization of disease phenotype is essential for testing therapies. Melanie J. Harrison, MD, MS, and Lisa D. Ravdin, PhD, discuss this issue with relation to central nervous system SLE. Finally, some new agents already in trials are described by Bryan D. Gescuk, MD, PhD, and John C. Davis, Jr., MD, MPH, MS, and William Stohl, MD, PhD.
Recent discoveries in genetics, molecular and cell biology, immunology, and etiology, reviewed at the SLE: Targets for New Therapeutics conference held at the National Institutes of Health, Bethesda, MD, in January 2002, have advanced optimism that a cure for lupus is within reach. The speakers at this NIH conference and scientists funded by various voluntary agencies have identified "targets" to aim for, to effect a lupus cure. What are these targets? Recent work has focused on identifying biologic molecules critical to the lupus disease process and on strategies to remove or neutralize them. Many such targets are known ( Table 1); most function as immune recognition sites or effectors. It is hoped that recognition of the critical target will allow development of a pharmacologic or biologic agent: "the cure."
However, lupus has a way of confounding experts. Like "target," "cure" has not been fully defined. Just 4 months after the NIH conference, a group of researchers sponsored by the American College of Rheumatology and co-sponsored by several groups and agencies, convened in Düsseldorf Germany, and found it difficult (but not impossible) to agree, even on measurement criteria for lupus response. Is cure the same as disease prevention? Is it amelioration or remission of established illness? Or is cure prevention or reversal of disease-caused complications?
To complicate the issue further, many events precede clinical recognition of disease (Fig. 1). Factors that influence the vulnerability to, and the course of lupus-perhaps the critical targets-and precede the diagnosis of disease include (genetic) susceptibility, a triggering agent, an incubation period (perhaps host or agent maturation or a requirement for a second trigger), and a phase of subclinical, incomplete, or undiagnosable disease (seropositivity in patients without clinical findings, or forme fruste, evolving and overlap syndromes). Factors that follow diagnosis include symptom recognition and documentation, subclinical damage (atherosclerosis, thrombosis, renal failure, osteoporosis, osteonecrosis, cognitive dysfunction), and development of symptoms related to damage. The search for a single target assumes the persistence and relevance of that target at each stage. Lupus is chronic, relapsing, and polymorphic. There may be several targets, and different targets in different phases of disease.
(Enlarge Image)
Relationships among potential targets in systemic lupus erythematosus. Years may evolve between exposure to a trigger agent and clinical symptoms. Note also that damage caused by disease or treatment of one organ system, eg, hypertension due to steroid treatment of nephritis, may lead to damage of another organ system, eg, cognitive dysfunction, independent of active systemic lupus erythematosus. Note also that organ systems may become involved independently and at different times. Identifying a single target for damage accrual of a single organ may give misleading information.
Disease activity in one organ system may not parallel disease activity in another system. For instance, thrombocytopenia and arthritis often develop and advance independently, as do renal and neurologic symptoms. It is also not evident that disease in different organ systems will have identical therapeutic targets, even when such disease activity is simultaneous. Because lupus evolves over years, short-term proxies for long-term response will be necessary; but, as yet, no validated proxies for outcomes exist. Whether an index of total disease activity is a more useful guide for clinical studies than measures of individual organ systems remains unclear. After much debate, the Düsseldorf group preferred organ-specific to global indices.
Thus, it is doubtful that the discovery of a single target, leading to a single cure, is either imminent or realistic over the long term. However, even if an all-encompassing cure is not "just around the corner," the future is quite bright. With remarkable progress in our understanding of how the immune system works, how genes modulate disease, and how to manufacture molecules that perform highly specific tasks, it is inevitable that the critical targets will be identified and lupus will continue to yield to our efforts. The challenge is to choose wisely among potential targets as the basic scientists expose more molecules relevant to disease, to ask clearly defined questions, and to develop an infrastructure for clinical investigation so that these questions can be answered. For some years, clinical investigation of lupus in the United States has been uncoordinated. The recent series of meetings offers a new consensus and a fresh start. With outcome measurement criteria in place and validated outcome proxies expected in the near future, we are poised to translate progress made at the molecular level into innovative tests and treatments for patients afflicted with lupus. We call on all physicians who care for lupus patients, and on the agencies-both government and private-charged with funding lupus research, to join in this task.
Abbreviations:SLE systemic lupus erythematosus
Source...