METHOD FOR THE TREATMENT OF JOINT DISEASES CHARACTERIZED BY UNWANTED PANNUS Background of the Invention Hyperplastic synovial joint diseases, such as rheumatoid arthritis, are disorders that can cause a condition known as synovial hyperplasia synovitis. Examples of such joint diseases include, e. g., inflammatory arthritides, including infection, deposition diseases such as amyloid arthropathy, as well as other disorders such as, neoplastic-like diseases such as pigmented villonodular synovitis. Synovial hyperplasia is an overgrowth of the inner layer of an articular capsule surrounding a joint. This inner layer is otherwise known as the synovial membrane. The synovial hyperplasia can further result in progressive destruction, deformity, and/or disability of the joint. The hyperplastic synovial membrane includes proliferation of the synovial cells and in many cases, inflammatory cells or proteins that may collect in the synovial membrane of the joint. The hyperplastic synovial membrane can be referred to as"pannus". Destruction or modification of the pannus can prevent joint destruction, deformity, and/or disability within the joint.

Summary of the Invention Methods of the invention are based in part on the discovery of a novel method for preventing the deterioration and/or destruction of joints which are afflicted with unwanted pannus, e. g., arthritis or other hyperplastic synovial joint diseases. Through the introduction of ultrasound energy into the joint to be treated, the pannus can be destroyed or modified to reduce the inflammatory response and prevent or decrease the amount of joint deterioration and/or destruction.

Accordingly, in one aspect, the invention provides a method of treating hyperplastic synovial joint diseases, e. g., arthritis. The method includes the steps of focusing a beam of ultrasound energy on the pannus so that the pannus is destroyed or modified.

In another aspect, the invention provides a method for the treatment of arthritis and other hyperplastic synovial joint diseases, comprising the steps of focusing a beam of ultrasound energy on the pannus so that the internal temperature of the pannus at a level sufficient to coagulate the pannus.

In still another aspect, the invention provides a method for the treatment of arthritis and other hyperplastic synovial joint diseases, comprising the steps of focusing a beam of ultrasound energy on the pannus so that the cavitation effects of the ultrasound energy destroys or modifies the pannus.

In yet another aspect, the invention provides a method for the treatment of arthritis and other inflammatory joint diseases, comprising the steps of focusing multiple short and high powered beams of ultrasound energy so that the pannus is vaporized.

In still yet another aspect, the invention provides a method for the treatment of arthritis and other inflammatory joint diseases, comprising the steps of utilizing a multiphase array to focus a beam of ultrasound energy on the pannus so that the pannus is destroyed or modified.

In an additional aspect, the previously described methods utilize a lens to focus the beam of ultrasound energy. In yet another additional aspect, the previously described methods utilize magnetic resonance imaging (MRI) as an image guidance system.

In still another additional aspect, the previously described methods control the MRI guidance system with a central processing unit for precise guidance. In still yet another additional aspect, the previously described methods do not damage the surrounding normal tissue or bone.

According to one aspect of the invention, the novel system may deliver ultrasonic energy in the range of about 0.2 to about 50 MHz. More particularly, a range of about 0.5 to about 20 MHz is preferred and still more preferable is a range of even about 1.0 to about 10 MHz.

According to another aspect of the invention, the ultrasonic energy is delivered in multiple treatments more than two minutes, one hour, or one day apart.

Conventional methods for destroying or modifying pannus have included open surgery and radiation therapy. The present invention provides an alternative to treating arthritis and other inflammatory diseases and uses noninvasive ultrasound energy to destroy or modify the pannus. Methods, as described herein, can replace invasive surgery and radiation therapy which are often used as a last resort for treatment. This novel therapy is noninvasive and controlled. Methods of the invention minimize the- cost of recovery. Because this treatment does not utilize ionizing radiation, it is repeatable.

Detailed Description of an Illustrative Embodiment of the Invention The ability of the ultrasound imaging modality for guidance of minimally invasive procedures has been shown in various disorders and particularly in conditions with joint involvement [Holsbeeck M, Introcaso JH, eds. Musculoskeletal Ultrasound, St. Louis: Mosby-Year Book Inc. (1991); Foldes K, Gaal M, Balint P et al., Ultrasonography after hip arthroplasty. Skeletal Radiol 21 : 297-9 (1992); Foldes K, Balint P, Balint G, et al., Ultrasound-guided aspiration in suspected sepsis of resection arthroplasty of the hip joint. Clin Rhem 14: 327-9 (1995); Foldes K, Balint P, Gaal M, et al., Nocturnal pain correlates with effusion in diseased hips. JRheumatol 19 : 56-8 (1992); Mayekawa DS, Ralls PW, Kerr RM et al. Sonographically guided arthrocentesis of the hip. J Ultrasound Med 8: 665-8 (1989)]. Another significant potential of ultrasound is the ability to produce coagulation necrosis in exposed tissue by high power focused sonication. By focusing high power ultrasound beams at a distance from the source, total necrosis of tissues lying within the focal volume can be achieved without damage to structures elsewhere in the path of the beam.

Because diagnostic ultrasound images are not sensitive enough to guide focused ultrasound thermal therapy, magnetic resonance imaging (MRI) has been used to guide this intervention [Cline HE, Hynynen K, Hardy CJ, et al., MR temperature mapping of focused ultrasound surgery. Magn Reson Med 31: 628-36 (1994); Cline HE, Hynynen K, Watkins RD, et al. A focused ultrasound system for MR imaging guide tumor ablation.

Radiology 194: 731-7 (1995)]. MRI thermometry based on temperature-dependent proton resonance frequency (PRF) has been shown to accurately reflect thermal changes

in tissue [Kuroda K, Abe K, Tsutsumi S, et al., Water proton magnetic resonance spectroscopic imaging. Biomed Thermol 13: 43-62 (1993); Chung AH, Hynynen K, Collucci V, et al., Optimization of spoiled gradient-echo phase imaging for in vivo localization of a focused ultrasound beam. Magn Reson Med 36: 745-52 (1996); Hindman JC. Proton resonance shift of water in the gas and liquid states. J Chem Phys 44: 4582-92 (1966)]. Phase images obtained before and after temperature elevation can be subtracted to acquire the phase difference, which is proportional to the temperature- dependent frequency change.

Synovial tissue proliferation and hyperplasia are characteristic signs of different types of arthritis, especially of rheumatoid arthritis. When synovial inflammation occurs, synovial cells of the membrane embodying the intimal and subintimal layer proliferate. The key role of the proliferating hyperplastic synovial tissue in joint destruction and deterioration suggests that early prevention of the synovial expansion is important in the treatment of inflamed joints.

Intraarticular injections of radionuclides (radio-synovectomy) have been shown to be effective in treating conditions with proliferative synovitis. However, the small tissue penetration and the leakage into the draining lymph nodes and circulation are particular disadvantages of this method [Gumpel JM, Roles NC. A controlled trial of intra-articular radiocolloids versus surgical synovectomy in persistent synovitis. Lancet 1: 488-9 (1975); Deckart H, Tamaschke J, Ett S, et al. Radiosynovectomy of the knee joint with gold-198 colloid, yttrium-90 ferric hydrate colloid and rhenium-186sulphide colloid. Radiobiol Radiother 3: 363-70 (1979)]. These problems have been partially overcome by using short-lived radionuclides and larger particulate carriers [Sledge CB, Zuckerman JD, Shortkroff S, et al. Synovectomy of the rheumatoid knee using intra- articular injection of dyprosium-165-ferric hydroxide macroaggregates. JBone Joint Surg (Am) 69: 970-5 (1987)]. However its use is limited to medical centers that are near nuclear reactors capable of producing radionuclides. Controversial results have also characterized the effectiveness of laser and photodynamic therapy in a few controlled studies [Hall J, Clarke AK, Elvins DM et al. Low level laser therapy is ineffective in the management of rheumatoid finger joints. Br JRheumatol 33: 142-7 (1994); Bliddal H,

Hellesen C, Ditlevsen P, et al. Soft-laser therapy of rheumatoid arthritis. Scand J Rheumatol 16 : 225-8 (1987)].

The present invention is based in part on the discovery of a novel method for treating arthritis and other hyperplastic synovial joint diseases. Through the noninvasive introduction of ultrasound energy into the joint, the hyperplastic synovial membrane or pannus can be destroyed or modified to reduce the growth or inflammatory response and prevent or decrease the amount of joint deterioration and/or destruction.

In a preferred embodiment of the invention, a spherical transducer which provides the ultrasound energy is focused on the area of the pannus to be destroyed or modified. The ultrasound energy provided by the transducer is preferably delivered to the pannus with a frequency in the range of 1.0 to 10 MHz. This energy destroys or modifies the pannus so that inflammation of the joint is reduced and joint mobility and range of motion is increased.

According to one embodiment of the invention, the novel system may deliver ultrasonic energy in the range of about 0.2 to about 50 MHz. More particularly, a range of about 0.5 to about 20 MHz is preferred and still more preferable is a range of about 1.0 to about 10 MHz.

In another aspect, the invention provides a method for the treatment of arthritis and other inflammatory joint diseases, comprising the steps of focusing a beam of ultrasound energy on the pannus so that the internal temperature of the pannus causes coagulation of the pannus. Preferably, the coagulation of the pannus includes the destruction or reduction in size of the pannus caused by the transformation of the liquid component of the pannus.

In still another aspect, the invention provides a method for the treatment of arthritis and other hyperplastic synovial joint diseases, comprising the steps of focusing a beam of ultrasound energy on the pannus so that the cavitation effects of the ultrasound energy destroys or modifies the pannus. Preferably, the cavitation effects of the ultrasound energy destroys or reduces the size of the pannus by forming cavities within the pannus tissue.

In yet another aspect, the invention provides a method for the treatment of arthritis and other hyperplastic synovial joint diseases, comprising the steps of focusing multiple short and high powered bursts of ultrasound energy so that the pannus is vaporized. Preferably, delivery of these multiple high powered bursts of ultrasound energy create an internal temperature in the pannus of between 55 and 100°C. Still more preferably, the ultrasound energy vaporizes the liquid component of the pannus tissue thus destroying or reducing the size of the pannus.

In still yet another aspect, the invention provides a method for the treatment of arthritis and other hyperplastic synovial joint diseases, comprising the steps of utilizing a multiphase array to focus a beam of ultrasound energy on the pannus so that the pannus is destroyed or modified. Preferably, the ultrasound phased array is comprised of various components. The ultrasound phased array system generally comprises a control system, controlling a channel driving system, that provides power to a matched ultrasonic transducer. The channel driving system comprises a power generation system, and a phase regulation system. The control system provides a power set point input and a feedback enable signal to the power generation, and a phase set point input and feedback select signal to the phase regulation system. The power generation system provides an output driver signal to the matched transducer, and provides a power feedback signal input to itself. The phase regulation system includes a phase feedback signal from the power generation system output or alternatively the matched transducer, to provide phase correction to the power generation system.

In an additional aspect, the previously described methods utilize a lens to focus the beam of ultrasound energy. Preferably, the lens is an acoustic lens that can be translocated or rotated in space to focus the wave of ultrasound energy at a particular focal point.

In still yet another aspect, the previously described methods do not damage the surrounding normal tissue or bone. Preferably, the ultrasound energy delivered to the joint is precisely controlled so as to destroy or modify only the damaged or inflamed or hyperplastic tissues and do not affect the surrounding areas of tissue or bone near the inflamed area to be treated which is not also diseased.

EXAMPLES EXAMPLE 1: Treatment of Pannus in Joints in Rabbits Antigen induced arthritis Five male New Zealand white rabbits weighing 3-5 kg were used. The research protocol was approved by the institution's Standing Committee on Animal Researclr.

Arthritis was induced as described by Zuckerman et al. [Zuckerman JD, Sledge CB, Shortkroff S et al. Treatment of antigen-induced arthritis in rabbits with dyprosium- 165-ferric hydroxide macroaggregates. J Orthop Res 7: 50-60 (1995)]. The rabbits were sensitized with 10 mg of ovalbumin emulsified with an equal volume of Freund's complete adjuvant (Sigma, St. Louis) given subcutaneously in several sites on the back.

Three weeks later, this sensitization all of the rabbits were sedated by intramuscular injections of 40 mg/kg Ketamin (Fort Dodge Laboratories, Fort Dodge, IA), and 10 mg/kg Xylazine (Fermenta Animal Health Company, Kansas City, MO). Five mg of ovalbumin in 0.5 ml of sterile, pyrogen-free saline solution were injected intra- articularly into both knees. Clinical signs of arthritis (joint swelling, redness, limitation of motion, pain reaction) were examined daily.

Sonication Sonications were performed 5-7 days after synovitis was induced. Animals underwent unilateral sonication. Ultrasound beam was targeted with an MRI-compatible focused ultrasound system, (General Electric Medical Systems) mounted in a standard MRI scanner table. A single-focus spherical transducer with 100 mm diameter, 80 mm radius curvature and 1.5 MHz resonant frequency to generate focuses ultrasound beams was used. After delineation of the target area in the MR images, a low power test (lOW/lOs) sonication was delivered to localize the ultrasound focus.

To test the ability of the ultrasound beam to necrotize synovial tissue, the target volume was sonicated with multiple, overlapping high power sonciations (60W/10s).

These parameters were chosen to produce necrosis of an area of 3-4 mm in diameter and about 6 mm in length [McDannold N, Hynynen K, Wolf D et al. MRI evaluation of thermal ablation of tumors with focused ultrasound. JMRI 8: 91-100 (1998)]. The

spacing between sonications was chosen to be the largest spacing that would allow for complete overlap of sonicated regions (e. g. for example, for a lesion with a 3 mm diameter the spacing was 3/V2). Seven to fifteen sonications were delivered to cover the selected synovial tissue depending on the size of the previously outlined tissue volume.

Cooling time between sonications was 30 seconds to prevent thermal buildup in the surrounding tissue. The body temperature was measured by using a rectal thermocouple.

MR Imaging MRI was tested to guide and control the procedure. The images were obtained in a 1.5 Tesla magnet (Signa, General Electric, Milwaukee, WI) using a 5 inch receive only surface coil placed beneath the knee. For tissue localization, T1 and T2 weighted fast spin echo (FSE) sequences were used. For Tl weighted images TR was 500 msec, effective TE (TE eff.) was 19 or 23 msec, and echo train length (ETL) was 4. For T2W images the corresponding parameters were TR 2200/TE eff. 69 or TR 3000/T eff. 95 or 105 msec and ETL 8. The following parameters were used for the T1W and T2W scans: field of view (FOV) was either 10 or 12 cm, slice thickness 3 mm with 1 mm inter--slice gap, imaging matrix 256 x 256,2 NEX for each sequence.

Phase-difference imaging was used to localize the focus and to measure the temperature rise. Temperature measurements were achieved by exploiting the temperature dependence of the proton resonant frequency (PRF) as described elsewhere [Cline HE, Hynynen K, Watkins RD, et al. A focused ultrasound system for MR imaging guide tumor ablation. Radiology 194: 731-7 (1995); Ishihara Y, Calderon A, Watanabe H et al. A precise and fast temperature mapping using water proton chemical shift. Magn Reson Med 34: 814-23 (1995)]. The phase shift was calculated using a fast spoiled gradient-echo sequence with the following parameters: TR 26.6 msec, TE 12.8 msec, flip angle 30, bandwidth 7.2 kHz, field of view 16 cm, matrix size 256 x 128, slice thickness 3 mm, scan time per image 3.4s. The frequency shift was found by multiplying the phase shift by 2p/TE.

To test the ability of MRI to reflect synovial tissue necrosis T1 W and T2W images were repeated after ultrasound exposure. Post-therapy T1W images were repeated after administration of intravenous bolus injection of gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) in the ear vein of the rabbit (dose, 0.1 mmol per kilogram of body weight).

Histology To assess the effects of sonication macroscopic and microscopic evaluation were performed. After the sonications, the animals were euthanized by intravenous overdose of Phenobarbital. The knee joint was then dissected from the surrounding tissues and the joint space examined grossly. Samples of synovial tissue were dissected from the joint and placed in a 10% phosphate buffered formalin. The specimens were processed for embedment and cut by microtome to 3-5 micron sections. Sections were stained with hematoxylin and eosin (H&E).

Results Partial synovial membrane destruction was achieved in five rabbits with experimentally induced arthritis of the knee by MRI-guided focused ultrasound. Gross and microscopic evaluation and MR signal alterations showed evidence of coagulation necrosis of the sonicated tissue in contrast to control specimens. Axial Tl-weighted contrast enhanced (Gd-DTPA) image of the knee after focal sonication showed no contrast enhancement in the coagulated tissue in contrast to the non-sonicated synovial tissue which is enhancing. Photomicrographs of the proliferative synovial tissue (Haematoxylin-eosin, magnification 20x) showed similar results when comparing the non-exposed hyperplastic synovial membrane with the sonicated synovial tissue showing coagulation necrosis. These findings were reproducible on subsequent experiments.

The presence of antigen-induced synovitis was proven by histological observation of the non-sonicated synovial tissue. Microscopic evaluation of the synovial tissue showed signs of inflammation (capillary hyperemia, villous formation, plasma cell

infiltration) with an excessive number of synovial lining cells. In some areas an increase in synovial cell size was also observed.

The effects of sonication were examined grossly and microscopically. Gross observation of the opened knee showed tissue necrosis in the sonicated area which was demarcated from the adjacent tissue. Microscopic evaluation of the dissected tissue revealed coagulation necrosis of the exposed synovium. It was characterized by celle with nuclear alterations (karyopknosis and karyolysis) and homogenous eosinophilic mass in areas of corresponding MR images. No structural damage of the capsule, ligaments and cartilage was observed.

On the pre-sonication images, the differentiation of the synovial tissue from the joint fluid on unenhanced T1-weighted images was not obvious because the proliferative synovium expressed an intermediate signal intensity compared to the low signal intensity of the joint fluid. The intermediate signal intensity of the synovial tissue was clearly differentiated from the bright signal intensity of joint fluid on T2 weighted FSE images.

On post-sonication images differentiation of the sonicated synovial tissue from the non-exposed tissue was feasible on all T2W and in all but one contrast enhanced Tl- weighted images. The differentiation however, was superior on contrast enhanced T1W images. On T2W post-sonication images, the regions of the sonicated tissue were dark with adjacent bright signal presumed to be edema. Within minutes following intravenous administration of contrast material the non-exposed hyperplastic synovial tissue exhibited contrast enhancement followed several minutes later by enhancement of the synovial fluid. The sonicated synovial membrane did not show contrast enhancement. In one experiment there was no evidence of any contrast penetration into the joint. However, the effects of the ultrasound exposure were evident by comparison of pre-sonication and post-sonication T2W images in this case. In two experiments, a small region of adjacent connective tissue (muscle) also showed signs of sonication on the post-sonication images.

The temperature rise from the baseline (37°C) for the synovial membrane was calculated by the method of Chung et al. [Chung AH, Hynynen K, Collucci V, et al.

Optimization of spoiled gradient-echo phase imaging for in vivo localization of a

focused ultrasound beam. Magn Reson Med 36: 745-52 (1996)] assuming the synovial membrane has similar tissue sensitivity to muscle (0.00909 ppm/°C). This calculation showed the mean temperature elevation from baseline to be +41.8°C with a range from +29°C to 55°C.

The results show that MRI-guided focused ultrasound produces noninvasively coagulation necrosis of inflamed synovial tissue and MR imaging canbe used to detect regions of synovial tissue destruction.

The inflamed synovial tissue appears intermediate in signal intensity on T1- weighted and T2-weighted images compared to a lower signal intensity of the effusion on T1W and higher signal intensity on T2W images [Winalski CS, Foldes K, Gravallese EM, et al. Disorders involving the synovial membrane: Magnetic resonance Imaging.

In: Stark-Bradley: Magnetic Resonance Imaging, Philadelphia: Mosby Year Book, Inc.

(In Press)]. Following contrast enhancement, the hypervascular synovial membrane enhances rapidly [Winalski CS, Aliabadi P, Wright JR, et al. Enhancement of joint fluid with intravenously administered gadopentetate dimeglumine: technique, rationale, and implications. Radiology 187: 179-185 (1993)] followed by slower enhancement of joint fluid.

Visible signs of thermal damage of the exposed synovial tissue was observed as high signal intensity with a bright ring-like appearance about the lesion on T2W images, which is in agreement with the literature [Cline HE, Schenk JF, Watkins RD, et al.

Magnetic Resonance guided thermal surgery. Magn Reson Med 30: 98-106 (1993)].

Furthermore, post-contrast T1W images clearly showed the lack of enhancement in the area of sonicated synovial tissue. The lack of enhancement in the sonicated regions suggests that the synovial membrane was no longer functional and probably necrotic.

Post-contrast images showed some small surrounding muscle damage was also observed in two animals in addition to the evidence of synovial tissue necrosis which was probably due to improper targeting due to animal motion.

Noninvasive MR-guided sonications have been shown to cause coagulative necrosis of different tissue masses [Hynynen K, Freund WR, Cline H et al. A clinical noninvasive MR imaging-monitored ultrasound surgery method. Radio-Graphics

16: 185-95 (1996)]. Ultrasound penetrates through soft tissue and can be focused to relatively small focal spots with dimensions of a few millimeters [Hynynen K, Freund WR, Cline H et al. A clinical noninvasive MR imaging-monitored ultrasound surgery method. Radio-Graphics 16: 185-95 (1996); Hynynen K, Vykhodtseva NI, Chung AH et al. Thermal effects of focused ultrasound on the brain: determination with MRI imaging.

Radiology 204: 247-53 (1997)]. Focused ultrasound beam can reach 10-15cm if there is a soft tissue window available for beam propagation. Thus, theoretically, deeply situated hip joint can also be reached if the skin-joint (skin-capsule) distance is within this range.

Thermal surgery by high power sonication destroys the tissue by the mechanism of coagulation necrosis in the range of 60°C to 70°C [Cline HE, Hynynen K, Hardy CJ et al. MR temperature mapping of focused ultrasound surgery. Magn Reson Med 31: 628-36 (1994)]. In regard to the sensitivity of the synovial tissue to the temperature sensitive images, an approximate mean peak temperature rise was calculated (41.8°C + the baseline) based on previously studied muscle sensitivity tests to imaging sequences.

It is thus seen that the invention efficiently attains the objects set forth above, among those made apparent from the preceding description. Since certain changes may be made in the above constructions without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense.

It is also to be understood that the following claims are to cover all generic and specific features of the invention described herein, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.

Having described the invention, what is claimed as new and desired to be secured by Letters Patent is: