The medical management of fibrodysplasia ossificans progressiva: current treatment considerations



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THE MEDICAL MANAGEMENT OF

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA:

CURRENT TREATMENT CONSIDERATIONS

Frederick S. Kaplan, M. D.1,2,3

Eileen M. Shore, Ph.D.1,2,4

David L. Glaser, M.D.1,2

Stephen Emerson, M.D., Ph.D. 3

And


The International Clinical Consortium

on Fibrodysplasia Ossificans Progressiva

September, 2003

From The Center for Research In FOP and Related Disorders,1

and The Departments of Orthopaedic Surgery,2 Medicine,3 and Genetics4

The University of Pennsylvania School of Medicine, Philadelphia, PA 19104.


Corresponding Author:


Frederick S. Kaplan, M.D.

Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine

The University of Pennsylvania School of Medicine

Department of Orthopaedic Surgery

Silverstein Two

Hospital of the University of Pennsylvania

3400 Spruce Street

Philadelphia, Pennsylvania 19104

Phone 215-349-8726/8727

Fax: 215-349-5928

Email: frederick.kaplan@uphs.upenn.edu

Reprint Requests: kamlesh.rai@uphs.upenn.edu

[Kaplan FS, Shore EM, Glaser DL, Emerson S, et al: The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Clin Proc Intl Clin Consort FOP 1(2):1-72, 2003]




INTRODUCTION 6

THE PATHOPHYSIOLOGY OF FOP 8

THE PATHOLOGY OF FOP 9

The Importance of Animal Models for FOP 11

The BMP4-Matrigel System: A Useful Animal Model 11

Lymphocytes as a Model System to Investigate FOP 11

Lymphocyte-Endothelial Cell Interaction: Early Markers of Inflammation 13

The Immune System and FOP 13



THE PATHOLOGIC AND PATHOPHYSIOLOGIC-BASED TREATMENT OF FOP 14

Gene Correction 14

Bone Marrow (Stem Cell) Transplantation 14

How Might Stem Cell Transplantation Successfully Treat or 15

Cure Fibrodysplasia Ossificans Progressiva? 15

Why Might Stem Cell Transplantation Fail to Successfully Treat or Cure 16

Fibrodysplasia Ossificans Progressiva? 16

What Would Favor the Therapeutic Index in the Direction of Stem Cell Transplantation for Fibrodysplasia Ossificans Progressiva? 17

Injury Prevention 18

Influenza and FOP 19

Corticosteroids 21

Mast Cell Inhibitors 22

Cyclo-oxygenase 2 inhibitors 24

Aminobisphosphonates 27

BMP Antagonists 37

Anti-angiogenic Agents 39

Thalidomide 41

Retinoids 42

Chemotherapy Agents and Radiation Therapy 43

Miscellaneous Agents 44

Muscle Relaxants 44


SPECIFIC TREATMENT CONSIDERATIONS 44

REPORT FROM THE INTERNATIONAL FOP CLINICAL CONSORTIUM: A GUIDE FOR CLINICIANS 45

CURRENT TREATMENT CONSIDERATIONS 46

CONCLUSIONS 48

ACKNOWLEDGMENTS 49

THE INTERNATIONAL CLINICAL CONSORTIUM ON FIBRODYSPLASIA OSSIFICANS PROGRESSIVA 50

REFERENCES 55

TABLE 1:CLASSES OF MEDICATIONS: FOP CLINICAL WORKSHOP 65

CLASS I MEDICATIONS 65

CLASS II MEDICATIONS 66

CLASS III MEDICATIONS 67



TABLE 2: WHAT TO DO IN COMMONLY ARISING CLINICAL SITUATIONS IN PATIENTS WITH FOP: 68

FIGURE 1: HYPOTHETICAL TREATMENT SCHEMA IN FIBRODYSPLASIA OSSIFICANS PROGRESSIVA 71

FIGURE 2: SELF-PERPETUATING FALL CYCLE IN PATIENTS WHO HAVE FIBRODYSPLASIA OSSIFICANS PROGRESSIVA: 72

ABSTRACT

The ultimate goal of research on fibrodysplasia ossificans progressiva (FOP) is the development of treatments that will prevent, halt, or even reverse the progression of the condition. In order to achieve that goal, it is imperative to determine the molecular and genetic cause of the disease, and to integrate those molecular and genetic insights into an understanding of the developmental, metabolic and physiologic pathways through which the putative damaged gene causes progressive and disabling heterotopic ossification.

Despite great strides during the past decade in understanding the molecular pathology and pathophysiology of FOP, few tangible advances have yet been realized in the treatment of FOP or in the prevention of its disabling complications. At the present time, there are no therapies with scientifically proven benefits for the prevention or treatment of FOP. The present lack of effective therapy for FOP arises primarily from the lack of definitive knowledge about the primary genetic damage that causes FOP and that orchestrates the complex developmental changes of the condition both pre-and postnatally. Additionally, the erratic natural history of the disease, the inability to obtain diagnostic biopsies at defined stages in the evolution of the disease, the lack of a genetically relevant animal model for drug testing, the lack of multi-generational families to study natural disease variability, and the lack of randomized double-blinded placebo-controlled studies further confound the efforts to establish a basis for rationale therapy in this complex disorder with genetic, developmental, post-traumatic, and autoimmune features.

Despite these daunting obstacles, the therapeutic horizon is infinitely brighter than it was a decade ago. Through the efforts of a collaborative international FOP research team dedicated to the eventual cure of FOP, major and fundamental advances continue to be made in understanding the molecular basis of the condition, and in understanding the detailed genetic, cellular, molecular, physiologic, and developmental changes that lead to the array of clinical changes that characterize FOP, and underlie the suffering of those who have it.

Profound insights in lymphocyte and mast cell biology, angiogenesis, apoptosis, bone morphogenetic protein (BMP) molecular cell biology, osteogenic induction, and endochondral bone formation have led to the development of treatment strategies that are at various stages of pre-clinical development, some of which will soon emerge into the arena of clinical testing. Identification of the gene that causes FOP will propel the development of a relevant genetic animal model that, when available, will dramatically accelerate the pace of drug testing and provide insight into the potential relevance of treatments such as bone marrow transplantation and definitive gene therapy with BMP (bone morphogenetic protein) antagonists or BMP receptor antagonists.

In the meanwhile, work continues in parallel on both the basic science and treatment fronts to advance the therapy of FOP. Despite the lack of definitive treatments at the present time, there have been numerous anecdotal reports of limited symptomatic benefit with various medications based on the results of uncontrolled studies. Further insight into some of these already available medications will await the design of randomized double-blinded placebo-controlled clinical studies, the most accepted method of obtaining truly useful information on the safety and efficacy of potential treatments.
In this article, we will review the scientific basis for considering various treatment and prevention options based upon the known pathology and molecular pathophysiology of FOP, while at all times keeping in mind that there are presently no proven preventions or treatments for the condition. Nevertheless, this document will attempt to present rationale guidelines for the use of medications in the symptomatic treatment of FOP based upon the current state of knowledge. This report is not intended to present the only approach for FOP, but rather is intended to represent a view, statement, or opinion of the authors which may be helpful to others who face similar situations.
Further advances in therapeutics await the unequivocal identification of the FOP gene, the development of relevant genetically-based animal models for drug testing, and the inception of urgently needed, well-designed, randomized, double-blinded, placebo-controlled studies to assess the various treatment and prevention options in a rigorous scientific manner. At the present time, we continue to focus our urgent attention in each of these areas.




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