MILWAUKEE SHOULDER SYNDROME* Fourier Transform

MILWAUKEE SHOULDER SYNDROME*

DANIEL J. McCARTY** MILWAUKEE In 1981 my colleagues and I encountered four elderly women with dysfunctional shoulder joints due to almost complete loss of the rotator cuff (1). Fluid from these joints avidly bound '4C ethane-1-hydroxy- 1,1,diphosphonate (EHDP) (2), a technique we developed at that time to screen joint fluids for ultramicroscopic calcium phosphate crystals (3). These crystals were formerly believed to be apatite (Gr. deceiver) but Fourier transform infrared spectrophotometric analysis of the crystal populations in these synovial fluid pellets showed a combination of carbonate-substituted hydroxyapatite and octacalcium phosphate or rarely tricalcium phosphate (4). As all 3 species are basic, as opposed to acidic phosphates, we have designated them generically as basic calcium phosphate (BCP) crystals. As the clinical, radiographic, and joint fluid findings in these patients were stereotypic and not described before we reported them as a syndrome dubbed "Milwaukee Shoulder" (1). With greater experience it became clear that the knee joint was also often involved in these patients (5, 6). As in patients with calcium pyrophosphate dihydrate (CPPD) crystal deposition (7), the patellofemoral and lateral tibiofemoral compartments are predominantly involved rather than the medial tibiofemoral compartment as in primary osteoarthritis (8). Patients with knee involvement associated with primary osteoarthritis become bow-legged (varus deformity), whereas those with knee involvement associated with Milwaukee Shoulder become knock-kneed (valgus deformity). Dieppe and his colleagues in the United Kingdom have described severe degenerative changes in hips, elbow and ankle as well as in knee and shoulder joints, calling the condition "apatite associated large joint lysis" (9). The features of Milwaukee Shoulder are described in this review together with the known pathophysiology and current and possible future therapies. Clinical Picture-We recently reported a total series of 30 patients with "Milwaukee Shoulder" and others have added 42 patients reported under a variety of descriptive terms (Table 1) (6, 9-12). The mean age of the patients in the combined reports is 72 years with a range of 50 to 90

* From the Division of Rheumatology, Department of Medicine, Medical College of Wisconsin. ** Address reprint requests to: Daniel J. McCarty, M.D., Will and Cava Ross Professor, Division of Rheumatology, Medical College of Wisconsin, 8700 W. Wisconsin Avenue, Milwaukee, WI 53226. 271 272 DANIEL J. MCCARTY

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0 C) MILWAUKEE SHOULDER SYNDROME 273 years. Women preponderate in a 4:1 ratio but this might be due in part to their greater longevity. Both shoulders were affected in 82 percent of our patients and in 64 percent of the combined series. The shoulder on the dominant side is uniformly involved in unilateral disease and the disease process is almost uniformly more advanced on the dominant side in bilateral disease. A single patient had cervical radiculopathy on the affected non-dominant side. Nearly all patients described pain during shoulder motion and at night while lying in bed. Pain was mild and intermittent in most instances except in one woman with polio-induced paraplegia who had used her arms for weight-bearing during transfer and to propel her wheelchair. Another woman had no pain at all despite dysfunction of the shoulder on the dominant side, and 3 others had symptomless involvement of the contralateral shoulder. All patients had restricted range of motion of the affected shoulder(s) associated with stiff (28 patients) or excessively mobile (2 patients) glenohumeral joints. Examination showed swelling due to an effusion in nearly all cases. This effusion was often of hydrops proportions. Synovial hyperplasia could sometimes be detected as well. Passive joint motion was often accompanied by palpable, and sometime audible, crepitus. Certain factors found in our patients may have contributed to the pathogenesis of their arthropathy (Table 2). Nearly a third of the total had experienced trauma on the affected side, most often a fall on the outstretched hand, or joint overuse such as in the case of the paraplegic woman already mentioned. Another patient had once operated a jack- hammer. Eight patients had evidence of underlying deposition of calcium pyrophosphate dihydrate crystals. Two patients had an associated cervical neuropathy due to syringomyelia and one a cervical radiculopathy due to spondylosis. Interestingly, all 8 men in our series had at least one identifiable predisposing factor.

TABLE 2 Identifiable Factors Associated with Milwaukee Shoulder/Knee Syndrome in This Group (15 Patients) and in the Entire Series of 30 Patients Factor Current Series Total Trauma/overuse 4* 9* Calcium pyrophosphate dihydrate 5* 8* crystal deposition Neuroarthropathy 2 3 Dialysis arthropathy 1 1 None 4 10 * One patient had two factors. Published with permission Arch Intern Med 1990; 150: 677. Copyright 1990, American Medical Association. 274 DANIEL J. MCCARTY Symptoms evolved slowly over a period of years in most patients making precise estimates of the time of symptom onset impossible. Many patients with this shoulder syndrome had symptoms of osteoarthritis in one or both knees but with more frequent patellofemoral and or lateral tibiofemoral compartment disease as discussed above. Radiographic Findings-Superior subluxation of the humeral head from the glenoid fossa, often forming a pseudoarthrosis with the distal clavicle and acromion, was found in essentially all affected shoulders (figure 1). Such displacement of the humeral head is only possible with widespread loss of the fibrous rotator cuff which normally fills this space. Glenohumeral joint degeneration, consisting of "joint space" narrowing indicative of cartilage loss and deformity of the humeral head was also found in nearly all cases. Partial bony collapse of the head was common. Small osteophytes were often present, but unlike primary osteoarthritis, were rarely prominent. Calcification of peri-articular soft tissues was noted in about 60 percent of affected shoulders in our series. Bony sclerosis and cyst formation in the humeral head were common as were erosions of the greater tuberosity at the site of insertion of the rotator cuff. Radiographs ofthe knees confirmed the clinical finding ofpredominant patellofemoral and lateral tibiofemoral, as well as medial tibiofemoral, compartment degeneration (figure 2 and 3). Synovial Fluid Findings-Fluid was obtained from all affected knee and shoulder joints. Leucocyte counts were low, none having greater than 800 cells per cmm, and nearly all of these cells were mononuclear (6). Erythrocytes were nearly always seen microscopically and blood-tinged or frankly sanguineous fluids were commonly encountered. Very large amounts of fluid up to 200 ml (hydrops) was not uncommon. Rupture of the distended joint into the chest wall occurred in 2 instances. I have seen a patient of Dr. Alfred Swanson's of Grand Rapids, where a fistulous tract developed between the joint and the subcutaneous tissues of the chest wall. The constant leakage of bloody fluid produced an amazing discoloration of the skin and a chronic anemia. (14C)EHDP binding was significantly elevated in nearly all fluids and correlated with the finding of microspheroidal particles corresponding to aggregates of ultramicrocrystals by scanning electron microscopy. The degree of (14C)EHDP binding corresponded to about 5 to 50 micrograms of standard hydroxyapatite per milliliter of synovial fluid. Direct chemical measurement of calcium and phosphorus in several washed pellets confirmed this estimate (2). The ('4C)EHDP technique is sensitive to about 2 micrograms of mineral per ml (2, 3). Interestingly the concentrations of BCP crystals found in synovial fluid are well within the range where MILWAUKEE SHOULDER SYNDROME 275

FIG. 1 AP roentgenogram of the right shoulder of an 84 year old woman who complained ofpain after use of her stiffened shoulder. The deformed humeral head is subluxed superiorly to form a pseudo-articulation with the coraco-acromial vault. Osteophytes are not prominent. Such subluxation is pathognomic of khe loss of the rotator cuff which normally fits the space between the humeral head and the acromion. these particulates produce striking biological effects on cells as discussed below. X-ray energy dispersive analysis showed a molar calcium/phosphorus of 1.2 to 1.7 compatible with varying proportions of CPPD (Ca2P207.2H20 giving a Ca/P of 1.0), OCP (Ca8H2(P04)6.5H20 giving a Ca/P of 1.33, and apatite (Ca5(P04)30H.2H20 giving a Ca/P of 1.67). Transmission election microscopy showed that the BCP crystal aggregates were composed of tiny plates (OCP) and needles (apatite) and were 276 DANIEL J. MCCARTY

FIG. 2 AP roentgenogram of both knees of one 81 year old woman showing lateral tibiofemoral compartment involvement. Osteophytes are not prominent. Published with permission Sem Arthritis Rheum 1984;14:36. invariably accompanied by particulate collagen. Analysis of several fluid pellets showed collagen types I and III, typical of synovial membrane, and type II, the major collagen of hyaline articular cartilage (2). Three of our original series of 4 patients represented rather florid examples of the condition (1). Activated collagenase was found in each instance in amounts greater than found in fluids from patients with active rheumatoid arthritis. Much lower collagenase activity was found in subsequent fluids and even this little was often in latent form (5, 6). A series of fluids studied using more precise methods has been reported recently from the United Kingdom (13). These workers found no active collagenase in any of 14 fluids from Milwaukee Shoulder joints nor in any of 10 fluids from rheumatoid arthritis patients. On the other hand, the low molecular weight collagenase inhibitor known as TIMP (tissue inhibitor of metalloprotease) was easily demonstrated in most fluids. As in rheumatoid arthritis where collagenase is also theoretically implicated as important in causing destruction of hard tissues, a microenvironment favorable for activation of this enzyme must be postulated (vide infra). A Historical Note-The gross pathologic features of "Milwaukee Shoul- der Syndrome" were described by Robert Adams, Regius Professor of MILWAUKEE SHOULDER SYNDROME 277

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FIG. 3 Lateral roentgenogram of the right knee of a 79 year old woman showing "patella- wrapped around the femur" appearance typical of patellofemoral compartment degeneration. 278 DANIEL J. MCCARTY Surgery at the University of Dublin, in both editions of his textbook, the first of which appeared in 1857 (14) accompanied by a splendid atlas of lithographs depicting various joints affected with inflammatory or degenerative types of arthritis. Adams, best known for his collaboration with Stokes in describing Stokes-Adams attacks, called the condition "chronic rheumatic arthritis of the shoulder." He recognized that the morbid changes were due to a disease process rather than to trauma as had been the contention of earlier authors, especially Sir Astley Cooper. Adams pointed out there was usually absence of a history of trauma, that the condition was often bilateral with identical morbid anatomical changes on both sides. Moreover he pointed out that the complete or nearly complete absorption of the intra-articular tendons and ligaments could not be explained by trauma. Adams wrote that "hydrops articuli" was usual in this condition with "up to one pint" of fluid in a single affected shoulder (14). He provided a vivid description of the excessive mobility of the affected shoulders due to glenohumeral subluxation. The loss of the intra-articular portion of the tendon of the long head of the biceps with reattachment of the extra- articular portion of the bicipital groove was described as a regular feature of the disease process (15). Probably no argument for the probability of collagenase activity could be stronger than his lithographs depicting this phenomenon. Pathogenesis- Werb and Reynolds had shown in 1974 that endocytosis of particles (latex beads) by cultured rabbit synovial cells was accompanied by augmented synthesis and secretion of neutral protease and collagenase (16). We postulated that BCP crystal microaggregates might represent in vivo equivalents of latex beads. When we added synthetic or natural BCP, calcium pyrophosphate or sodium urate to synovial cells in culture, they did indeed behave as latex beads, stimulating eight to tenfold increases in protease synthesis (17). Like latex beads, they also stimulated phospholipase A2 to release large amounts of arachidonic acid which was converted to prostaglandin (PG)E2 and other prostanoids by cyclo- oxygenase. When synovial tissue containing BCP crystal aggregates or hyaline cartilage containing CPPD crystals were incubated with partially purified mammalian collagenase in vitro, crystals were "strip-mined" from the tissue and released into the surrounding medium (18). Thus, we envisioned a vicious cycle with augmented protease and prostaglandin production after crystal endocytosis by synovial cells, which in turn released more crystals and particulate collagens. The cumulative effect would be perceived clinically as degeneration of joint tissues and lysis of the rotator cuff and biceps tendon. The initial reason for formation. of a BCP mineral phase was, and still is, unknown. MILWAUKEE SHOULDER SYNDROME 279 Injection of uniformly trace radiolabelled BCP or CPPD crystals into the synovial space in rabbit joints showed that all nuclide was within the synovium in 24-48 hours (19-21). All dissolution occurred within the synovial cell. Maneuvers which should have affected extracellular crystal solubility had no effect on clearance rate constants whereas maneuvers affecting intracellular events did have such effect. Clearance of labelled CPPD crystals was also measured in human knee joints (19). The half life of CPPD crystals in human joints was 1-3 months, in rabbit joints about 3 weeks. Clearance of one half of the much smaller BCP crystals from rabbit joints took about 10 days (22). The long-life of intracellular crystals is important as their biological effects are relentless until complete dissolution occurs. As shown in figure 4, BCP crystals also stimulated membrane bound

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FIG. 4 Working schema of biological effects of crystals on certain anchorage-dependent cells. Rod-shaped crystal = monosodium urate; aggregated crystals = basic calcium phosphate; C.O. = cyco-oxygenase; ER = endoplasmic reticulum. Both urate and calcium phosphate (or pyrophosphate) crystals stimulate phospholipases A + C as well as increase mRNA for collagenase. Monosodium urate crystals produce breaks in the phagolysosomal membrane after their protein coat has been digested, killing the cell. They also stimulate the release of interleukin-1 (not shown). Crystals containing calcium are much less membranolytic, do not stimulate release of IL-1 but are powerful growth factors of the competence type. Both endocytosis and dissolution are required for such growth factor activity. 280 DANIEL J. MCCARTY phospholipase C, producing inositol trisphosphate and diacylglycerol from the liberated phosphatidylinositol (23). Crystals containing calcium, but not other crystals or particulates, stimulated the transcription of the "competence" oncogenes, c-fos, c-myc and c-jun in much the same time sequence that followed stimulation by platelet-derived growth factor (PDGF) (24). [C-fos and c-jun proteins form a heterodimer, AP-1, which binds to DNA as a transactivator of the genes for proteases such as collagenase, stromolysin, and gelatinase]. Like PDGF, crystals containing calcium are sufficient to cause cells to move from Go to G1. A "progression" factor such as somatomedin C (insulin-like growth factor 1) is then needed for the cell to tranverse late G1, S, G2, and mitosis (25). Crystals containing calcium are dissolved within the phagolysosome by hydrogen ions secreted by an ATP driven proton pump which is in the phagolysosomal membrane (26-29). Endocytosis is a necessary pre- requisite to dissolution (29). Lysosomotropic weak bases, such as the anti-malarial hydroxychloroquine or ammonium chloride inhibit the proton pump and block crystal dissolution (28, 29). Agents which block crystal dissolution also effectively block crystal-induced mitogenic "competence" although proto-oncogene activation is unaffected (24). PDGF induced competence is also unaffected by these agents. Down regulation of protein kinase C by phorbol esters, (a DAG analog) blocked both oncogene transcription and competence induced by calcium crystals but not by PDGF (30). Thus competence induced by calcium containing crystals is diphasic: (1) an early event at the plasma membrane which requires protein kinase C activation and (2) a later event which depends on crystal dissolution in the phagolysosome. Recent data indicate that another compound, phosphocitrate, blocks both protease and proto-oncogene transcription induced by calcium crystals but not the effects of classical growth factors such as PDGF (31). The mechanism of its action remains unclear. Phosphocitrate, like chlo- roquine, is a potentially useful therapeutic agent in conditions like Milwaukee Shoulder where chronic stimulation with calcium-containing crystals seems likely to play an important role in producing devolutionary joint changes. Therapy-Treatment currently is supportive and symptomatic. Reduc- tion of joint use seems useful. For example, purchase of an electric wheelchair for one patient, a paraplegic woman who was in constant pain, reduced the demands on her shoulders to the point where she became nearly asymptomatic. Intra-synovial injection of microcrystalline suspensions of corticosteroid esters followed by joint rest for 3 weeks and prescription of non-steroidal anti-inflammatory drugs also provided symptomatic relief. Joint replacement is a theoretical consideration but MILWAUKEE SHOULDER SYNDROME 281 this is technically difficult without the stabilizing influence of the rotor cuff. Moreover, most of these patients are elderly and frail.

COMMENT Basic calcium phosphate crystals, ie. carbonate substituted hydroxyapatite and octocalcium phosphate, occur in a variety of disorders, including advanced osteoarthritis, calcific peri-arthritis, calcific tendon- itis, calcinosis circumscripta and calcinosis universalis. BCP crystal aggregates have been found in synovial fluid in several different clinical settings, including acute gout-like attacks, erosive polyarticular disease, and osteoarthritis (31). Acute pseudopodagra in young women is a rare, recently described syndrome associated with BCP crystal deposits (32). Milwaukee Shoulder is somewhat unique in the degree of dissolution of collagenous structures. Osteoarthritis of the shoulder is relatively rare and is characterized by sclerosis of the humeral head, prominent osteophytes and a well preserved rotator cuff (33). Cartilage loss is usually localized. In Milwaukee Shoulder there is widespread loss of cartilage, marked focal softening of the bony humeral head, and relatively small osteophytes. Focal osteopenia may be so marked that the humeral head is partially collapsed; it may be soft enough to cut with a knife at surgery (10). The one feature of the disease as originally described that has not stood the test of time is the finding of active collagenase in the joint fluid. The evidence for a role of this enzyme in the widespread collagen loss in tissues exposed to synovial fluid is still circumstantial. The dose- related stimulation by calcium containing crystals of increased protease synthesis and secretion by synovial cells in tissue culture and the con- sistent finding of intracellular BCP crystals in synovial biopsies from our patients by electron microscopy certainly supports the concept of the vicious cycle discussed above. The latent and active forms of collagenase are known to be in equilibrium. Cys73 binds a zinc atom in the active site. Agents which "activate" collagenase merely shift the equilibrium toward the active form by interfering with Cys73-zinc binding (34). Thus partial denaturation of the enzyme protein could perturb binding by physical separation, whereas oxidants, disulfides, alkylating agents, mercury (II) or gold (I) compounds bind the sulfur residue on Cys73; limited proteolysis, a time-honored method of activation, simply removes Cys73 itself. Perhaps the active enzyme is absorbed from the joint fluid by its substrate or perhaps, as has been postulated in rheumatoid arthritis, it is active in a microenvironment. The recent data clarifying the molecular mechanism of acti- 282 DANIEL J. MCCARTY vation would seem "made to order" for a microenvironment. Further work is needed to test these hypotheses.

REFERENCES 1. McCarty DJ, Halverson PB, Carrera GF, et al. Milwaukee shoulder: association of microspheroids containing hydroxyapatite crystals, active collagenase, and neutral protease with rotator cuff defects, I: clinical aspects. Arthritis Rheum 1981; 24: 464. 2. Halverson PB, Cheung HS, McCarty DJ, et al. Milwaukee shoulder: association of microspheroids containing hydroxyapatite crystals, active collagenase and neutral protease with rotator cuff defects, II: synovial fluid studies. Arthritis Rheum 1981; 24: 474. 3. Halverson PB, McCarty DJ. Identification of hydroxyapatite crystals in synovial fluid. Arthritis Rheum 1979; 22: 389. 4. McCarty DJ, Lehr JR, Halverson PB. Crystal populations in human synovial fluid: identification of apatite, octacalcium phosphate, and tricalcium phosphate. Arthritis Rheum 1983; 26: 1220. 5. Halverson PB, McCarty DJ, Cheung HS, et al. Milwaukee shoulder syndrome: 11 additional cases with involvement of the knee in 7. Semin Arthritis Rheum 1984; 14: 36. 6. Halverson PB, Carrera GF, McCarty DJ. Milwaukee shoulder/knee syndrome: 15 additional cases and a description of contributing factors. Arch Intern Med 1990; 150: 677. 7. Ryan LM, McCarty DJ. Calcium pyrophosphate crystal deposition disease (pseudogout: articular chondrocalcinosis). In: McCarty DJ, ed. Arthritis and Allied Conditions. Philadelphia: Lea & Febiger, 1989: 107. 8. Halverson PB, McCarty DJ. Patterns of radiographic abnormalities associated with basic calcium phosphate and calcium pyrophosphate dihydrate crystal deposition in the knee. Ann Rheum Dis 1986; 45: 603. 9. Dieppe PS, Doherty M, MacFarlane DG, et al. Apatite associated destructive arthritis. Br J Rheumatol 1984; 23: 84. 10. Neer CS, Craig EV, Fukuda H. Cuff tear arthropathy. J Bone Joint Surg Am 1983; 65: 1232. 11. Weiss JJ, Good A, Schumacher HR. Four cases of 'Milwaukee Shoulder' with a description of clinical presentation and long-term treatment. J Am Geriatr Soc 1985; 33: 202. 12. Newman JH, Chavin KD, Chavin IF. Milwaukee shoulder syndrome: a new crystal- induced arthritis syndrome associated with hydroxyapatite crystals: a case report. Del Med J 1983; 55: 167. 13. Dieppe PA, Cawston T, Mercer E, et al. Synovial fluid collagenase in patients with destructive arthritis of the shoulder joint. Arthritis Rheum 1988; 31: 882. 14. Adams R. Treatise on Rheumatic Gout. 2nd ed. London, England: John Churchill & Sons; 1873: 91. 15. McCarty DJ. Robert Adams' rheumatic arthritis of the shoulder or Milwaukee shoulder revisited. J Rheumatol 1989; 16: 668. 16. Werb Z, Reynolds JJ. Stimulation by endocytosis of the secretion of collagenase and neutral protease from rabbit synovial fibroblasts. J Exp Med 1974; 140: 1482. 17. Cheung HS, Halverson PB, McCarty DJ. Release of collagenase, neutral protease and prostaglandin from cultured mammalian synovial cells by hydroxyapatite and calcium pyrophosphate dihydrate crystals. Arthritis Rheum 1981; 24: 1338. MILWAUKEE SHOULDER SYNDROME 283 18. Halverson PB, Cheung HS, McCarty DJ. Enzymatic release of microspheroids containing hydroxyapatite crystals from synovium and of calcium pyrophosphate dihydrate crystals from cartilage. Ann Rheum Dis 1982; 41: 527. 19. McCarty DJ, Palmer DW, Halverson PB. Clearance of calcium pyrosphosphate dihydrate (CPPD) crystals in vivo studies using 169 Yb labelled triclinic crystals. Arthritis Rheum 1979; 22: 718. 20. McCarty DJ, Palmer DW, James C. Clearance of calcium pyrophosphate dihydrate (CPPD) crystals in vivo II. studies using triclinic crystals doubly labelled with 45Ca and 85Sr. Arthritis Rheum 1979; 22: 1122. 21. McCarty DJ, Palmer DW, Garancis JC. Clearance of calcium pyrophosphate dihydrate crystals in vivo III. effects of synovial hemosiderosis. Arthritis Rheum 1981; 24: 706. 22. Palmer DW, McCarty DJ. Clearance of 85Sr labelled calcium phosphate crystals from rabbit joints. Arthritis Rheum 1984; 27: 427. 23. Rothenberg RJ, Cheung HS. Rabbit synoviocyte inositol phospholipid metabolism is stimulated by hydroxyapatite. Amer J Physiol 1988; 254: (Cell Physiol)(23): C554. 24. Cheung HS, Mitchell PG, Pledger WJ. Activation of proto-oncogenes by BCP crystals: effect of beta-interferon. Cancer Res 1989; 49: 134. 25. Cheung HS, Van Wyk JJ, Russell WE, et al. Mitogenic activity of hydroxyapatite: requirement for somatomedin C. J Cell Physiol 1986; 128: 143. 26. Evans RW, Cheung HS, McCarty DJ. Cultured human monocytes and fibroblasts solubilize hydroxyapatite crystals. Cakc Tissue Intl 1984; 36: 645. 27. Evans RW, Cheung HS, McCarty DJ. Cultured canine synovial cells solubilize 45Ca labelled hydroxyapatite crystals. Arthritis Rheum 1984; 27: 829. 28. Owens JL, Cheung HS, McCarty DJ. Endocytosis precedes dissolution of basic calcium phosphate crystals by murine macrophages. Calc Tissue Intl 1986; 38: 170. 29. Cheung HS, McCarty DJ. Mitogenesis induced by calcium-containing crystals: role of intracellular dissolution. Exp Cell Res 1985; 157: 63. 30. Mitchell PG, Pledger WP, Cheung HS. Molecular mechanism of basic calcium phosphate crystal-induced mitogenesis: role of protein kinase C. J Biol Chem 1989; 264: 14071. 31. Cheung HS, Sallis JD, Mitchell PG, et al. Inhibition ofbasic calcium phosphate crystal- induced mitogenesis by phosphocitrate. Biochem Biophys Res Commun 1990; 171: 20. 32. Fam AG, Rubenstein J. Hydroxyapatite pseudopodagra: a syndrome of young women. Arthritis Rheum 1989; 32: 741. 33. Neer CS. Replacement arthroplasty for glenohumeral osteoarthritis. J Bone Joint Surg 1974; 56A: 14. 34. Springman EB, Angleton EL, Birkedal-Hansen H, et al. Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a "cysteine switch" mechanism for activation. Proc Natl Acad Sci (USA) 1990; 87: 364. DISCUSSION Billings (Nashville): Dr. McCarty are these joints as painful as they would appear? The knee, for example, is weight bearing very painful? McCarty: They're not as painful as they look. The deformities are much more grotesque than the pain. In fact, we've seen the condition in the shoulder as completely painless. Billings (Nashville): It makes you feel as though there is some type of neurological lesion. They look like Charcot-type joints. McCarty: I agree. We do know that the CPPD crystals can be associated with joints that look just like a neuroarthropathy with perfectly normal nervous system by any criteria. 284 DANIEL J. MCCARTY Hunter (Charlottesville): It's rather interesting that as I listen to this, the more I thought about it, the more I heard myself described. I finally decided it was certain when you mentioned the longhead of biceps. I have two "unicapses" now and my shoulders, after walking on crutches for 70 years, have been disintegrating. They haven't quite gotten to flail. All I want to know is whether there is anything you can do about it at age 77. I'm not going to have my shoulders operated on, but is there any noninvasive or reasonable thing for me to do? McCarty: No. At this point, the normal prostheses don't do well in shoulders without rotator cuffs. There are constrained prostheses that are attached that are reasonable alternatives. We have had four of our cases operated on with reasonable results. Most of the patients are too frail to take a chance on surgery. One woman, for example, was in an ordinary wheelchair and a switch to a motorized chair helped a great deal. She was in the most pain of anyone. She is a remarkable lady who had polio. She raised three children from a wheelchair, and a remarkable person. She is married to a veteran with no legs. What we hope is that we can interrupt this process with drugs. What I didn't have time to get into is that we have some drugs now that totally shut off the biological effects of crystals. Phosphacitrate, for example, which has been used to inhibit renal stones, totally inhibits the mitogenic response and collagenase mRNA. Rochester (Charlottesville): It sounds as though what would be highly relevant from the clinical and therapeutic point of view, would be to recognize this disease very early. How do you do that? McCarty: That's the problem with rheumatology. We are always there on the fifth of July, wondering what happened on the fourth. You're never there when a disease is starting, and particularly with something like this which is relatively slow moving. Perhaps we can identify patients that had their dominant side involved. We might be able to intervene and save the opposite shoulder. It also may be possible in those who are destined to get knee arthritis to do something early on. I'm not totally pessimistic about the chances of doing something about this. If we think our knowledge about rheumatoid arthritis is primitive, the knowledge of this condition is much more so.