31 EROSIVE ARTHRITIS ASSOCIATED WITH APATITE CRYSTAL DEPOSITION H. RALPH SCHUMACHER, JEFFREY L. MILLER, CHARLES LUDIVICO, and RALPH A. JESSAR Apatite crystals can be associated with erosive arthritis. This report describes 3 such patients, 2 of whom had idiopathic apatite crystal deposition and 1 who had apatite related to renal failure and chronic dialysis. Diagnosis was delayed for several years in 1 patient. Roentgenograms showed calcifications in all patients. Synovial fluid had non-birefringent chunks and globules suggestive of apatite. Diagnosis was established by electron microscopy in all 3 patients and verified by x-ray diffraction in 2. Hydroxyapatite crystals have been widely recognized in association with bursitis (l), periarthritis (2), and inflammatory reactions in subcutaneous sites (3), but only recently in actual arthritis (4-6). In most reports, periarthritis or arthritis has been intermittent and apparently nonerosive. In our study of 1977 (4)only 1 patient of the 5 with idiopathic apatite deposition had any chronic arthritis and roentgenographic evidence of joint damage. This report describes further details on this patient and 2 others with documented apatite crystals in joint fluid and erosive arthritis in one or more joints with no other identified cause for arthritis. MATERIALS AND METHODS The patients described here were identified from a group of 21 in whom we have now confirmed the presence of From the Philadelphia VA Medical Center and the Hospital of the University of Pennsylvania, Philadelphia, PA. H. Ralph Schumacher, MD; Jeffrey L. Miller, MD; Charles Ludivico, MD; Ralph A. Jessar, MD. Address reprint requests to H. Ralph Schumacher, MD, Professor of Medicine, Director, Arthritis-Immunology Center, VA Medical Center, Philadelphia, PA 19104. Submitted for publication April 4, 1980; accepted in revised form September 8, 1980. Arthritis and Rheumatism, Vol. 24, No. 1 (January 1981) synovial fluid apatite crystals. Effusions were examined as wet preparations with a Zeiss compensated polarizing light microscope. When sufficient fluid was available, leukocyte counts were done by using 0.3% saline as a diluent with a standard hemocytometer. Wright’s stained smears were made of each fluid and Von Kossa stain for phosphate was done on two smears. The remaining fluid was centrifuged, supernatant decanted, and the pellet fixed promptly in one half strength Karnovsky’s glutaraldehyde-paraformaldehydefixative. After 15 minutes fixation, the pellet was minced in 1 X 1 mm pieces and fixed for an additional 4 hours at room temperature. Pieces were then washed four times during 1 hour in 0.1M cacodylate buffer at pH 7.4, dehydrated with alcohol, placed in a 50% propylene oxide and Epon 812 mixture for 2 hours, and then embedded in Epon 812. Thin sections were cut with a diamond knife and examined in a Zeiss EM 10 transmission electron microscope with a 60 kV beam. Specimens were examined both unstained and after staining with uranyl acetate and lead citrate. Other thin sections were examined unstained with the EM 10 by using a 30 mmz Kevex Si (Li) dispersive x-ray detector interfaced with a multichannel analyzer and a computer system. Any crystals found were analyzed by using a spot size of 0.5-3 pm diameter and 120 to 200-second analysis times. The globular material aspirated from the joints of patients 2 and 3 was air dried and examined by x-ray diffraction. A Debye-Scherrer powder camera of 114.6 mm diameter using Chromium K alpha radiation with a vanadium filter was used. Measurements were based on wave length 2.29092 A. The specimen was exposed for 20 hours at 50 kV and 20 mamp. CASE REPORTS Patient 1. McJ was a 53-year-old black man, a manual laborer, who presented to the emergency room of Philadelphia VA Medical Center on August 19, 1977 with a 5-month history of episodes of pain and swelling on the right second proximal interphalangeal (PIP) joint. Mild swelling remained between painful episodes 32 Figure 1. Roentgenogram of patient 1 showing penarticular calcification, periosteal reaction, and bony erosion at right second PIP joint. that subsided spontaneously or with low doses of aspirin. Four days before being seen he developed dramatically increased pain at the second PIP with swelling that extended to the dorsum of the hand. He gave a history of intermittent severe shoulder pain with no bouts in the last 2 years, but denied any other diseases or specific trauma to the finger. He was gifen colchicine 6 mg orally over 12 hours with complete resolution of the pain over 2 days. On August 23, he returned and was noted to have only slightly warm fluctuant swelling of the right second PIP with minimal tenderness, slight limitation of elbow extension, and otherwise normal findings of a physical examination. There was no enlargement of other finger joints, sclerodactyly, or muscle weakness. Roentgenograms of the shoulders were normal, but the hands revealed an arc of amorphous calcification on the ulnar side of the right second PIP with marginal erosion and periosteal reaction (Figure 1.) Hematocrit was 38%; leukocyte count (WBC) was 6, 100/mm3with 5 1% polymorphonuclear leukocytes, 44% lymphocytes, 3% eosinophils, and 2% monocytes. Serum creatinine was 1.2 mg% and uric acid 7.7 mg%. Latex fixation for rheumatoid factor was negative. The fluctuant PIP joint was aspirated and yielded 1 cc of opaque gray-white, bloodtinged fluid. Examination of a wet smear revealed no birefringent crystals under compensated polarized light, but large masses of shiny-appearing 2-lop chunks and SCHUMACHER ET AL globules as described with hydroxyapatite (4) were present. These stained brown with the Von Kossa stain. Differential cell count on a Wright’s stained smear of synovial fluid showed 50% large mononuclear cells, 25% monocytes, 5% lymphocytes, 18% polymorphonuclears, and 2% eosinophils. A Sudan stain was positive in the large mononuclear cells, suggesting that they were monocyte-derived phagocytic cells (7). Some shiny globules seen in these cells stained purple with Wright’s stain. A leukocyte count was not possible. Electron microscopy confirmed the presence of tiny apatite-like crystals of 100-250 A diameter. Synovial fluid culture was negative. The patient was given colchicine 0.5 mg orally twice daily but discontinued this because he felt no further pain. He was seen once on October 21, 1977 when bony enlargement and slight limitation of flexion was noted at the right second PIP, but there was no soft tissue swelling. He was then lost to followup. Patient 2. MR, a 50-year-old white woman, was admitted to the Hospital of the University of Pennsylvania (HUP) in June 1976 with a 1-week history of arthritis of the second left proximal interphalangeal joint. Since the age of 25 the patient had intermittent pain, swelling, and warmth of elbows, wrists, and small joints of her hands. The episodes characteristically involved one joint, although multiple joint attacks had been noted, and subsided after 3 to 4 days. In 1951 and 1953 she received x-ray radiotherapy to elbows and hands “for arthritis and calcium deposits,” which were said to disappear after therapy. In August 1959 she was admitted to HUP for evaluation of recurrent pain and swelling of her upper extremity joints. Her medication included high dose aspirin and dexamethasone 1.5 mg/day. She was hirsute with moon facies. Her joint examination was negative for inflammation or deformity. The hemoglobin was 12.6 gm%, WBC 9,900 per mm3, and erythrocyte sedimentation rate (ESR) (Wintrobe) 9 mm/hour. She had a negative LE prep, rheumatoid latex fixation, serum protein electrophoresis, and serologic test for syphilis. Thyroid I3’I uptake was normal. Serum calcium, phosphorus, BUN, sugar, and 24-hour urinary calcium and phosphate were normal. Roentgenograms of hands and elbows revealed periarticular calcifications near metacarpophalangeal joints, wrists, and the right elbow. The patient was said to have palindromic rheumatism and gold sodium thiomalate therapy was initiated. In August 1960 she was readmitted because of recurrent joint pains despite the treatment with gold. Gold was continued 25 mg weekly, and hydroxy- EROSIVE ARTHRITIS Figure 2. Wet preparation of synovial fluid from patient 2 showing angular and globular dark or light appearing material with some clumps. This is the typical light microscopic appearance of clumps of apatite (4). Two erythrocytes are clearly circular. (Magnification X 33 for arthritis. She denied Raynaud’s phenomenon, serositis, alopecia, oral ulcerations, recent rashes, swallowing difficulty, or shortness of breath. Blood pressure was 155/88, pulse 76 per minute, temperature 99°F. Positive physical findings included markedly erythematous, fluctuant, tender swelling of her second PIP with very limited range of motion. The right thumb IP was fused. A small right knee effusion was present, but the joint was nontender and had full range of motion. Laboratory studies revealed hemoglobin 13.3 gm%, WBC 12,600/mm3 with 65% neutrophils, 11% monocytes, and 24% lymphocytes. Westergren sedimentation rate was 2 mm/hour, antinuclear antibody was negative, calcium 9.4 mg%. BUN 19 mg%, potassium 2.8 mEq/100 ml. Aspiration of the left second PIP joint fluid revealed 1.0 cc of very viscous creamy white fluid. loo.) chloroquine 200 mg twice a day was started. In August 1963 she required readmission for excruciating right wrist pain and swelling. Roentgenograms of the right hand revealed soft tissue swelling with multiple areas of soft tissue calcification. Swallowing function on cinefluorogram was normal. The patient gradually responded to a course of ACTH therapy and was discharged. Gold and hydroxychloroquine were discontinued. Without treatment except for ACTH at the time of bouts, she had episodic arthritis with symptom-free intervals up to 3 years. Acute episodes lasting several days to weeks involved wrists, several metacarpophalangeal (MCP) and PIP joints, shoulders, and elbows. In October 1969 she had a flare of the left third PIP joint which was treated with an intraarticular injection and intramuscular ACTH at home. She suffered intermittently from acute arthritic flares of the right thumb interphalangeal (IP) joint and left second PIP, which were treated with intraarticular steroids. In July 1975 a right thumb IP fusion was performed for painful subluxation of the joint. Histologic examination of the joint revealed thickened synovium with fibrosis, fragments of dead bone, and amorphous debris staining positive with the Von Kossa stain for calcium phosphate. She was then free of joint symptoms until about 1 week prior to admission when she noted acute onset of painful swelling of the second left PIP. Several days after an intraarticular steroid injection the joint flared again. Aspiration of the second left PIP revealed thick creamy white fluid, and the patient was admitted with concern about a possible septic arthritis. Family history was negative Figure 3. Calcification and marked joint destruction of left second PIP of patient 2, 1976. There is also a small periarticular calcification at the DIP. 34 Figure 4. Small calcifications and bony erosions at MCP joints of patient 2, 1969. A large amount of angular, globular or amorphous nonbirefringent material was present (Figure 2) which interfered with the determination of the joint fluid WBC. Von Kossa stain was positive. Intermixed with the above material were strongly negative and positive birefringent rodlike, chunky, and ovoid shaped crystals, not resembling urate or calcium pyrophosphate (CPPD) crystals. Electron microscopy identified apatite-like needle and rod shaped crystals which were confirmed to be apatite on x-ray diffraction (4). Calcium to phosphorus molar ratio by electron probe elemental analysis was 1.64:l. Gram stain was negative for bacteria and joint fluid cultures were negative. Right knee synovianalysis revealed 2 cc of straw-colored synovial fluid with a good mucin clot and no cells or crystals. Hand roentgenograms revealed marked periarticular calcification about the second PIP with destruction of the joint space and adjacent bone (Figure 3). The second distal interphalangeal (DIP) joint also had faint periarticular calcification and irregular joint space narrowing. Calcifications were also found at other fingers, the hip greater trochanters, and subacromial bursae. Review of 19651969 roentgenograms documented erosions at several MCP joints with associated calcifications (Figure 4). These still persisted and had worsened in the 1976 roentgenograms. The patient was started on oral colchicine 0.6 mg every hour until she developed gastrointestinal intolerance at the eleventh tablet; the colchicine dose then was changed to 0.6 mg twice a day. During the initial 3-day treatment with colchicine, the patient had a slow but steady improvement in the left second PIP swelling. A SCHUMACHER ET AL second joint aspiration on the fourth hospital day still revealed thick fluid that was brownish and culture-negative. The right knee effusion did not reappear and she was discharged greatly improved. She was started on indomethacin 25 mg 4 times a day with continued resolution of the inflamed PIP. Further attacks have occurred in a pattern similar to that established, but frequently with possibly more rapid resolution after colchicine or indomethacin therapy. Patient 3. BB was a 54-year-old white man who presented in July 1978 with 1% years of persistent chronic pain and swelling in knees, elbows, shoulders, and MCP joints. Ibuprofen and aspirin 3.2 gm/day were of no help. He had been on chronic hemodialysis for 2 years for renal failure secondary to polycystic kidney disease. Parathyroidectomy with single-gland forearm implantation had been done in February 1978 for Figure 5. Calcifications at the left first, fourth, and fifth MCP joints, ulnar side of the carpal-metacarpal area, and at several PIP joints in patient 3. There is erosion most evident at the ulnar side of the distal end of the fourth and fifth metacarpal bones. EROSIVE ARTHRITIS Figure 6. Apatite crystals from patient 3 with straight or slightly curved, dense needle shaped crystals of lW250A diameter. Crystals are surrounded by finely granular material. (Electron micrograph magnification X 26,000.) 35 SCHUMACHER ET AL 36 secondary hyperparathyroidism; histologic examination of the gland showed only hyperplasia. Carcinoma of the prostate had been treated with local radiation I year previously. Plasma studies in August 1978 revealed total calcium 9.6 mg/100 ml, ionized calcium 3.6 mg/100 ml (normal 3.74.50); phosphorus 5.9 mg/100 ml; parathyroid hormone level was 301 units per ml (normal 163-347). On physical examination we identified multiple deposits of a firm nodular substance around the first and third right and first, fourth, and fifth left MCP joints, within and adjacent to the elbows, adjacent to the shoulders, and on the posterior chest wall. The metacarpophalangeal joints and the knees were tender. Roentgenograms revealed radiopaque material in the MCP joints and in the other palpable deposits, There were erosions in the MCP joints, especially on the ulnar side (Figure 5) and at the lateral side of the femoral condyle of the right knee. Material aspirated from the third right MCP joint, right elbow, and right shoulder confirmed the hydroxyapatite crystal deposition with shiny globules (4) seen by light microscopy and typical needles by electron microscopy (Figure 6) (4). Electron probe analysis of material from MCP and shoulder showed calcium :phosphorus molar ratios of 1.48: 1-1.69 : 1 which is very similar to identically handled known apatite (4). No birefringent crystals were found. Therapy with indomethacin 25 mg 3 times a day and naproxen 250 mg twice daily for 1 week was not helpful. Injections of triamcinolone tebuate and I% procaine were given into the MCP joint, right shoulder, and left knee without changing the deposits and slightly decreasing the discomfort for only 1 week. Further examinations have revealed increasing large deposits in the first right and left metacarpophalangeal joints, and in the right third and fourth MCP joints. Severe claudication recently developed in both legs. DISCUSSION The recent demonstration of hydroxyapatite crystals with the synovial fluid (43) as well as in periarticular tissues (2) raised the possibility that they might be associated with a wide spectrum of intraarticular diseases similar to gout or pseudogout. We first recognized apatite crystals in acute arthritis mimicking acute gout or pseudogout (4). The 3 patients reported here illustrate that apatite can also be associated with erosive and destructive joint changes, as can chronic urate and CPPD diseases (8). Mechanisms involved may well be similar, because clumps of apatite are found phago- cytized by leukocytes in some effusions (4) and can be shown to be phagocytized in vitro (9) and to induce inflammation when injected into dog knees, much as do urate and CPPD crystals (4). The patients in this study were evaluated for other causes of erosive arthritis and none were found. Secondary hyperparathyroidism in patient 3 was considered a possible cause for joint erosions, but an elevated parathormone level was not found and there were no typical subperiosteal erosions. The possibility that calcifications adjacent to the erosions were only secondary to bony erosion was considered very unlikely since 2 of the 3 patients also had documented episodes of symptomatic periarticular calcifications in sites away from bone. Patients 1 and 2 had no disease known to be associated with apatite crystal deposition. Patient 3 on renal dialysis is another example of the recognized association of renal failure and dialysis with apatite deposition in periarticular (10) and intraarticular sites (4). We have also previously reported a destructive arthritis associated with apatite crystals in patients with mixed collagen-vascular disease (11) and have seen other examples in scleroderma. In such patients, the etiology of the erosion is not as clearly associated with crystal induced inflammation, but must be suspected since the socalled collagen diseases otherwise usually have few joint erosions ( 12,13). Intraarticular joint injections are a recognized cause of periarticular calcifications (14,15) and may contribute to more rapid joint destruction. Antecedent injections given in patient 2 may have contributed to her severe second PIP changes, but injections had not been given at other sites with generally more subtle erosions and calcifications. The previous steroid injections could have contributed some of the unidentified birefringent crystals in this patient; however, it should be noted that apatite laden effusions may also occasionally include some clumps with birefringence (4). No urate or CPPD crystals were found in any of our 3 patients by light or electron microscopy. Diagnosis of apatite-associated arthritis and periarthritis can be suspected on roentgenograms or by examination of aspirated fluid for angular or irregular nonbirefringent chunks, including some which are larger than cells. Such clumps of apatite crystals stain with hematoxylin, and for calcium and phosphate with Von Kossa stain (4). Identity of clumps as apatite can be supported by electron microscopy (4) and electron probe analysis, as described in the case reports. Apatite is most definitively confirmed if sufficient numbers of EROSIVE ARTHRITIS 37 crystals are present to be studied by x-ray diffraction 15. This confirmation was performed in cases 2 and 3. Treatment of acute episodes with colchicine or indomethacin along with aspiration has seemed helpful in 2 of our patients and in others reported (4,16), although many attacks also subside spontaneously. No effective long-term drug therapy is known, although continued administration of indomethacin may possibly be helpful. REFERENCES 1. Pinals RS, Short CL: Calcific periarthritis involving multiple sites. Arthritis Rheum 7:359-367,1964 2. McCarty DJ, Gatter RA: Recurrent acute inflammation associated with focal apatite crystal deposition. Arthritis Rheum 9:804-819, 1966 3. Schumacher HR, Schimmer B, Gordon GV, Bookspan MA, Brogadir S, Dorwart BB: Articular manifestations of polymyositis and dermatomyositis. Am J Med 67:287292, 1979 4. Schumacher HR, Somlyo AP, Tse RL, Maurer K: Arthritis associated with apatite crystals. Ann Intern Med 87:411416, 1977 5. Dieppe PA, Crocker P, Huskisson EC, Willoughby DA: Apatite deposition disease-a new arthropathy. Lancet 1:266-269, 1976 6. Fam AG, Pritzker KPH, Stein JL, Houpt JB, Little AH: Apatite associated arthropathy: a clinical study of 14 cases and of 2 patients with calcific bursitis. J Rheumatol 6:461471. 1979 7. Traycoff RB, Pascual E, Schumacher HR: Mononuclear cells in human synovial fluid: identification of lymphoblasts in rheumatoid arthritis. Arthritis Rheum 19:743748, 1976 8. Schumacher HR: Pathogenesis of crystal induced synovitis. Clin Rheum Dis 3:105-131, 1977 9. Maurer KH, Schumacher HR: Hydroxyapatite phagocytosis by human polymorphonuclear leukocytes. Ann Rheum Dis 38:84-88, 1979 10. Moskowitz RW, Vertes V, Schwartz A, Marshall G: Crystal induced inflammation associated with chronic renal failure treated with periodic hemodialysis. Am J Med 47:450-460, 1969 11. Reginato A, Schumacher HR: Synovial calcification in a patient with collagen vascular disease: light and electron microscopic studies. J Rheumatol4261-27 I, 1977 12. Labowitz R, Schumacher HR: The articular manifestations of systemic lupus erythematosus. Ann Intern Med 74:911-921, 1971 13. Schumacher HR: Joint involvement in progressive systemic sclerosis (scleroderma): a light and electron microscopic study of synovial membrane. Am J CLn Pathol 60593-600, 1973 14. Hardin JG, Greller JM, Andriopoulos N: Controlled study of the long-term effects of “total hand” injection-a preliminary report (abstract). Arthritis Rheum 19:800801, 1976 15. McCarty DJ: Treatment of rheumatoid joint inflammation with triamcinolone hexacetonide. Arthritis Rheum 15:157-173, 1972 Thompson GR, Ting YM, Riggs GA, Fenn ME, Denning 16. RM: Calcific tendinitis and soft tissue calcification resembling gout. JAMA 203:464-472, 1968 Practical Neurology, and Metabolism and Endocrinology The University of Washington will hold a seminar in Practical Neurology and one in Metabolism and Endocrinology February 21-28, 1981 in Hawaii. For further information contact Continuing Medical Education, University of Washington, Seattle, WA 98195, or call (206) 543-1050.