Seminars in

ARTHRITIS

AND RHEUMATISM December

VOL 22, NO 3

The Arthritis ByAdolf0

of Familial

AMILIAL Mediterranean fever (FMF) is an inherited disorder characterized by recurrent, self-limited attacks of abdominal, chest, or articular pain and associated with fever and a predilection for people of Mediterranean ancestry.’ The arthritis of FMF consists of acute attacks of pain and swelling of one articulation at a time, sometimes related to minor trauma and subsiding in 2 to 3 days.2 Protracted articular attacks have been described, especially in the knee and hip.” The main clinical observation is the absence of permanent sequelae, even in long-standing recurrent cases. The radiographic appearance is not specific and is characterized by soft tissue swelling and transient osteoporosis; in chronic cases, joint space narrowing, osteophyte formation, and sclerosis4 are observed. Treatment consists of administration of nonsteroidal antiinflammatory drugs (NSAIDs) during an attack and colchicine as preventive therap~.~ Renal amyloidosis is the principal cause of mortality in patients with FMF and is noted especially in Jews from northern Africa.‘j Seminarsin ArfhrifisandRheumatism,

Fever

Garcia-Gonzalez and Michael H. Weisman

Familial Mediterranean fever (FMF) is a disease of unknown etiology and pathogenesis. In addition to fever, arthritis is among its most frequent manifestations. The arthritis of FMF is typically an acute, episodic, self-limited process with no sequelae. The radiographic features of FMF arthritis are usually limited to transient, often severe osteoporosis. Synovial fluid analysis many mimic septic arthritis with very high white blood cell counts; cultures are uniformly negative. The course of FMF is almost always benign, with no residual articular incapacity. Some patients, limited to certain ethnic groups, develop renal amyloidosis. Colchicine therapy modifies the natural history of the disease by decreasing

F

Mediterranean

1992

the attack frequency and preventing amyloid deposition. At present, a lipocottin deficiency appears to be the likely candidate for a pathogenic mechanism. An unusual case with dramatic periarticular features (periostitis) and a protracted course with an excellent response to synovectomies is repotted here. There is no explanation for the exuberant periarticular bone formation noted in this case, but a variety of recently discovered growth factors may be implicated. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: INDEX WORDS: Arthrititis; familial Mediterranean fever; periostitis; colchicine.

We describe a patient with FMF who developed periarticular inflammation, including periostitis, around multiple affected joints. This patient did not respond to NSAIDs, colchicine, or steroids; synovectomy controlled his articular disease. In this report we review the radiology, histology, etiopathogenesis, natural history, and treatment of the arthritis of FMF. The unique aspects of this case, including the periarticular manifestations and response to surgical treatment, may provide clues to further investigations as well as additional treatment options.

From the Division of Rheumatology, Department of Medicine, University of California, San Diego, San Diego, California. Adolf0 Garcia-Gonzalez, MD: Fellow, Rheumatology Division; Michael H. Weisman, MD: Professor of Medicine, Rheumatology Division. Address reprint requests to Michael H. Weisman, MD, UCSD Medical Center, #8418, 225 Dickinson St, San Diego, CA 92103. Copyright 0 1992 by W.B. Saunders Company 0049-0172l92/2203-0001$5.00/0

Vol22, No 3 (December), 1992: pp 139-150

139

GARCIA-GONZALEZ

140

AND WEISMAN

CASE REPORT

The patient is a 25year-old Jewish white man whose parents are from Morocco. He has two brothers; the younger has FMF characterized predominantly by attacks of fever and abdominal pain. The patient’s disease began in infancy with attacks of fever and abdominal pain. The earliest manifestations were abdominal, occurring every other week, lasting 2 to 3 days, and associated with fevers to 101 and 102°F. Over the years the abdominal manifestation have persisted and the arthritis has progressed. The joint disease began later, when he was 8 years old, with acute arthritis of the left knee. Since then he has had acute attacks at different locations (knee, ankle, elbow, wrist), one at a time, approximately three times a month, lasting 3 to 4 days each. In 1977, at age 13 years, he began colchicine therapy, later stopping it because of perceived lack of efficacy. In 1980, after multiple episodes of left knee inflammation and no response to medical treatment with NSAIDs, he underwent left knee synovectomy. Since then no further inflammation in the left knee has occurred. In October 1987 he developed acute right knee pain and effusion; synovial fluid aspiration showed 64,000 white blood cells (WBC)/mm3 with 95% polymorphonuclear leukocytes (PMN) and negative cultures. Radiographic studies showed heterotopic bone formation in the distal part of the femur, a large effusion, and soft tissue swelling (Fig 1). A frontal radiographic view of the pelvis showed right sided sacroilitis (Fig 2), but lumbar spine films were normal. After a course of antibiotics, a right knee synovectomy was performed. A severe acute and chronic inflammatory reaction was present in the synovium (Figs 3 and 4); amyloidosis was absent. At that time, urine protein determination was normal. Right knee inflammation reccurred 2 weeks postoperatively, and synovial fluid analysis again showed acute inflammation with negative cultures. No additional acute attacks affecting the right knee have taken place subsequently. The patient presented to the University of California, San Diego, Medical Center in August 1988 because of right ankle swelling of 2 months’ duration. Low-grade fever and pain and swelling of the first and second toes of the

Fig 1:

Lateral view of the right knee showing

heterotopic

bone formation

(arrow), soft tissue

swelling, and effusion (arrowhead).

right foot had taken place for 5 days. The right ankle pain and swelling restricted the patient to bed. Physical examination showed temperature, 37.8”C; pulse, lOO/min; blood pressure, 152/80 mm Hg. Knee examination disclosed bilateral quadriceps atrophy, synovectomy scars, no effusion, full range of motion, and crepitus. The right ankle was markedly swollen and painful to touch. The first metatarsophalangeal (MTP) joint was tender. Radiographic evaluation was positive only for soft tissue swelling and effusion. The patient was given NSAIDs with no response. Synovial fluid analysis showed 62,000 WBC/mm3, 90% PMN, good mucin clot, 2.0 g/dL protein, and 70 mg/dL sugar. Cultures were negative, including anaerobes, mycobacteria, and fungi. HLA-B27 antigen was absent. Antinuclear antibody and rheumatoid factors

THE ARTHRITIS OF FAMILIAL

Fig 2:

MEDITERRANEAN

FEVER

141

Anteroposterior

projection of the pelvis, remarkable for right-sided sacroiliac

joint erosions,

irregular

margins,

and

sclerosis (arrow).

were negative, and the patient had extraordinarily high levels of serum amyloid A (SSA) [ 158 to 507 ug/mL; normal range, 1 to 10 Fg/mL (Jean Sipe PhD, Department of Biochemistry, Boston University School of Medicine, Boston, MA)]. Several intraarticular injections of steroids were performed without clinical benefit. After 3 months of unsuccessful medical treatment, right ankle synovectomy was performed. Histopathologic findings showed a mixture of acute severe and chronic mild inflammation (Figs 5 and 6);

tissue cultures were negative for bacteria and mycobacteria. Since the operation no further inflammation of the right ankle has occurred. The patient resumed colchicine therapy in January 1989 and continued to do well until September 1989, when he developed left elbow arthritis characterized by severe pain and very prominent articular as well as periarticular swelling. Radiographs showed an articular effusion and prominent periosteal reaction along the shaft of the distal humerus (Fig 7). Intraarticular ste-

Fig

3:

A photomicro-

graph of the right knee synovium shows fibrin exudate and thick-walled blood vessels (hematoxylin-eosin stain; original magnification x 100).

142

GARCIA-GONZALEZ

Fig 4:

AND WEISMAN

A higher-power

photomicrograph from another area of the same specimen

as

in

Fig

3

shows plasma cells, lymphocytes, and histocytes near vessels with plump endothelial toxylin-eosin

lining (hemastain; origi-

nal magnification

roids were injected on four separate occasions over 7 months with no appreciable benefit. On one occasion, fluid aspiration revealed 200,000 WBC/mm3 and negative cultures. After 7 months of unsuccessful treatment with colchitine and analgesics (occasionally narcotics), the left elbow arthritis subsided and a follow-up radiograph showed resolution of the periostitis (Fig 8). In September 1990, the patient developed severe pain and inflammation of the right sternoclavicular joint; radiographic results were

Fig 5:

Low-power

tomicrograph

pho-

of the right

ankle synovium showing abundant fibrin bordered by granulation tissue containing inflammatory cells (hematoxylin-eosin stain; original magnification x40).

x 160).

normal. The patient continues to experience right sternoclavicular joint pain and swelling and recurrences of left elbow arthritis. Lateral radiographs of the right knee show resolution of the periostitis with apposition of new bone over the distal portion of the femur (Fig 9). Results of current radiographic examination of the left knee, right elbow, and left ankle are normal. The patient continues to take colchicine and narcotic analgesics with little, if any, control of the arthritis.

THE ARTHRITIS OF FAMILIAL

Fig 6:

High-power

MEDITERRANEAN

FEVER

143

mag-

nification of the inflammatory

cell

infiltrate

granulation

and

tissue show-

ing PMNs in addition lymphocytes,

to

histocytes,

and plasma cells (hematoxylin-eosin; magnification

original x 160).

COMMENT

The Arthritis of FMF

Most information regarding the arthritis of FMF comes from Israel and Arab countries,1-3T6,7 where the disease is endemic; additional important reports originate from Middle Eastern immigrants to the west coast of the United States.* The clinical picture of FMF is unique and specific. The attacks appear as peritonitis, synovitis, or pleuritis and are often mimetic. Each attack presents in a similar manner, even in patients who experience all of the different forms of the attacks.6 Peritoneal attacks occur in 95% of cases and are the first manifestation of the disease in 55%. They are characterized by a combination of signs and symptoms that suggest acute abdominal catastrophe, often resulting in surgery. Pleural attacks occur in 40% of cases and frequently are accompanied by pleural effusion. Arthritis is present in 75% of cases of FMF and is the presenting sign in 26% of the affected population2 Joint involvement begins at an early age; more than 50% of patients are 10 years old or younger at the time of the initial attack,6 and the mean age at onset is 4.9 years.’ Three unique clinical types of arthritis have been described: acute, chronic, and abortive.2,9 The acute attack, which represents 95% of the reported cases, is characterized by short-

duration, self-limited episodes of arthritis usually lasting less than a week. The frequency of attacks is variable and often unpredictable. The patient can be asymptomatic for months or even years and have recurrence of articular manifestations after a long period. Some precipitating factors are claimed such as excessive exertion, prolonged standing,6 insignificant trauma, stresslo fat-rich diets,” or tuberculin injections.** The arthritis has an abrupt onset with severe pain in and around the affected articulation, often keeping the patient immobile. A large effusion is almost always present, and there is a surprising absence of redness and heat of the same magnitude. The articulation and the surrounding structures are extremely tender to palpation. Muscle atrophy appears early and progresses rapidly. During the initial hours, the patient develops a low-grade fever which subsides as the arthritis progress. An association with erysipelaslike rash, affecting the lower extremities predominantly during the first days of articular inflammation, has been described.*,’ The most often affected joints are in the lower extremity (in order of descending frequency: knee, ankle, hip); the upper extremity is also involved, with the same predilection for large joints (shoulder, elbow, wrist). Other articulations such as the proximal interphalanged joint of the toes and the sacroiliac and sternoclavicu-

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AND WEISMAN

cases. Articular inflammation that lasts more than a month has been called protracted arthritis3 and its average duration is 6 months; longer courses are not uncommon. The attack begins similarly to an acute episode, but there is no resolution and chronic monoarthritis is the result. Fever is not present once long-standing arthritis is evident. The effusion is often large, and pain is severe, leading to incapacity of the patient and periarticular muscle atrophy. The knees and hips represent 75% of all cases of chronic arthritis; the ankle, wrist, shoulder, sacroiliac, sternoclavicular, MTP, elbow, and temporomandibular joints are sometimes involved. The main feature of the long-standing arthritis of FMF is full recovery of the patient without any sequelae, with the exception of hip involvement; 84% of the affected hips during protracted arthritis develop residual incapacity, ranging from limitation of motion to complete ankylosis of the joint. The third type of arthritis is the abortive attack whose frequency is not

Fig 7: Lateral view of the left elbow with prominent periosteal reaction along the shaft of the distal

humerus

and radial head (arrows).

Effusion was seen on the original film but was not reproduced on this photograph.

lar joints can be involved in acute attacks; however, these are mostly affected when the arthritis becomes long-standing.3 A single articulation is usually affected at one time, but when inflammation in the first has not completely concluded, a second one may begin to become inflamed. Polyarticular involvement is present in 20% of affected children, simulating other entities such as acute rheumatic fever, juvenile rheumatoid arthritis, and ankylosing spondylitis.’ The same joint is often involved each time, but during the course of this long-standing illness it is not unusual for different articulations to be affected. Between crises the patient is completely asymptomatic. Long-standing arthritis accounts for 5% of

Fig 8:

A left elbow radiograph taken 7 months

after resolution of the acute arthritis attack. The lamellar appearance of this distal humerus shaft with underlying lucency (arrow) is consistent with new bone formation.

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FEVER

145

ance is reversible when the inflammatory process has not lasted long enough to cause degenerative changes.3 The hip joint consistently develops the most severe residual incapacity, not only from degenerative changes but also from radiographic evidence of avascular necrosis. Synovial Fluid

Synovial fluid analysis indicates severe acute inflammation. WBC counts range from 200 to 1,000,000/mm3 with a mean of 140,000/mm3 and high predominance of PMNs. Other descriptions include good mucin clot, slight elevation of total protein levels, and normal glucose levels. Cultures are always negative. WBC counts in excess of 100,000/mm3 frequently suggest infection, and patients are often subjected to prolonged antibiotic therapy in spite of negative cultures. Histology Fig 9:

A follow-up

3 years after

right knee radiograph taken

Fig 1 shows

resolution

of the

periostitis with apposition of new bone over the distal portion of the femur (arrow).

known because its only manifestation gia.6

is arthral-

Radiology

Radiological findings are compatible with the disease in the protracted form but not specific in the acute form. The most frequent findings are soft tissue swelling and transient osteoporosis, usually greater than expected compared with other forms of acute monarthritis.13 In the chronic form, a close direct prognostic relationship has been described for radiographic changes and poor outcome of the articulation. A most striking feature is the progression of osteoporosis not only in the affected joint but also in the remainder of the limb. Lytic intraarticular changes in metatarsophalangeal and sacroiliac joints are also noted in protracted attacks. Most patients with chronic arthritis develop degenerative changes such as narrowing of the joint space, osteophytosis, and sclerosis.4 In some cases in which sacroilitis is present, spondylitic changes can be found.6 The radiographic appear-

Histological examination of the synovium shows acute inflammatory changes with vascular dilatation, infiltration with PMN leukocytes, and proliferation of synovial mononuclear lining cells.6 In long-standing cases, a chronic inflammatory pattern is observed with perivascular lymphocytic aggregations and proliferation of granulation tissue. These changes show remarkable reversibility during the intercritical period, even in protracted arthritis. Inheritance

The disease is common among Jews, especially the Sephardic ethnic group from northern Africa. Sephardic Jews are the most often affected, representing approximately 60% of reported cases. Among non-Jewish groups afflicted by FMF, 30% of cases occur in Armenians and the remainder (10%) in people from different countries around the Mediterranean Sea.6 The pattern of inheritance has been analyzed in several reports6*14g15 and from the evidence of a lower-than-expected incidence for a pure autosomal recessive inheritance appears to be attributable to a single recessive autosomal gene with variable penetrance. However, in several families two or more generations are involved. In spite of evidence for a genetic basis

146

of the disease, multiple reports have failed to find any correlation with the HLA system.i4 Some authors have postulated that a polygenic type of inheritance exists in which the penetrance of the disease is influenced by a variety of environmental factors,15 based on the occurrence of more severe forms of the disease in the familial cases than in isolated nonfamilial cases. Diagnosis

FMF is diagnosed solely on a clinical basis. From the description of the cases by Sohar et al in 1967,6 few changes have been made to the six inclusion criteria used in their report. To establish the diagnosis according to Sohar et al, criteria 1 through 3 must be met; criteria 4 through 6 are of value in situations of diagnostic uncertainty. The criteria are as follows: 1, short attacks of fever recurring at various intervals; 2, painful manifestations in the abdomen, chest, joints, or skin accompanying the fever; 3, absence of any causative factor or any pathological finding, in vivo or postmortem, capable in itself of explaining the clinical picture; 4, amyloidosis clinically of the systemic hereditofamiliar form and chemically by amyloid protein A in serum; 5, features of autosomal recessive inheritance; 6, preference for people of Mediterranean stock, particular Sephardic Jews and Armenians. Our patient fulfills criteria 1 through 3 and 6, a familial pattern is shown by the presence of recurrent fever and abdominal pain in a younger brother. Several tests described as diagnostic tools for the evaluation of patients with suspected FMF are based on provocative challenges or putative specific immunologic abnormalities. The “metaraminol provocative test,” described in 1984,i6 consists of the infusion of 10 mg of this sympathomimetic substance, followed by a typical attack of FMF within 48 hours. High sensitivity and specificity are reported by the authors; side effects included headaches and transient palpitations. However, severe complications such as bigeminal rhythm and angina pectoris have been described.” Another diagnostic procedure is the determination of “dopamine+-hydroxylase,“ls an enzyme released simultaneously with catecholamines. Both of these provocative tests are based on the hypothesis that the pathogenesis of FMF is related to an abnormality in

GARCIA-GONZALEZ

AND WEISMAN

catecholamine metabolism.” However, there is evidence that this purported abnormality is not the principal defect in patients with FMF.20 Immunologic abnormalities that have been proposed as a diagnostic aid in this disease are high serum levels of C4 and other inflammatory proteins such as haptoglobin, a2-macroglobulin,*l and amyloid A protein.** Assays for these proteins appear to be more in concordance with newer proposed mechanisms for the pathophysiology of FMF. The sensitivity and specificity of these diagnostic tests remain to be verified. Course

FMF is almost always benign. Its clinical manifestations, although dramatic, are not life threatening. The main characteristic of the arthritis is complete recovery. With the exception of the protracted arthritis of the hip, there are no sequelae or residual incapacity of the affected joint.6 However, a small group of patients develop the severe and life-threatening complication of amyloidosis,5 and the amyloidosis present in FMF appears to be identical to what is generally referred to as secondary amyloidosis. They have a common serum protein precursor, the acute-phase reactant serum amyloid A.23 An important associated finding in patients with FMF is the presence of ankylosing spondylitis (AS).24 Fourteen cases are available for review, most of them from French literature? Of the patients in whom HLA-B27 assay was performed, none had positive results. The diagnosis of AS was based on the radiographic presence of sacroiliitis and spine involvement. When the relationship was noticed, the diagnosis of FMF had been made several years before the findings of AS were encountered. In the absence of HLA-B27 as a marker of disease susceptibility, it is likely that the cases reported were not true AS. It is possible that the presentations of FMF in these cases were atypical with more than the usual spine and sacroiliac joint involvement. This possibility is supported by the fact that most of the initial radiological sacroiliitis findings in 27 patients with FMF were inconsistent after the observers had undergone training sessions.*” This variation in radiological diagnosis was not seen in control patients with true AS.

THE ARTHRITIS OF FAMILIAL

MEDITERRANEAN

FEVER

Pathophysiology

The exact mechanism for the pathogenesis of the disease is not known. Since the original paper by Sohar et a1,6 an inborn error of metabolism has been postulated; however, several different hypotheses have been advanced related to an underlying immunologic abnormality.27 Among the more important findings in FMF is the absence of a protein that inhibits neutrophi1 chemotaxis by antagonizing the complement-derived inflammatory mediator C5a. This C5a inhibitor is produced under normal circumstances by synovial and peritoneal fibroblasts but not by skin fibroblasts. Initially, Matzner et a128 showed the absence of C5a inhibitor in patients with FMF using inhibition of neutrophi1 chemotaxis, and more recently the same author, using 125recombinant C5a, was able to corroborate the lack of CSa-inhibitory activity in synovial and peritoneal fluids of these patients.29 Other components of the complement system have been studied using hemolytic tritation. There is an increase in blood components especially involving the C4 fraction; results of analysis of Cl esterase inhibitor by enzymatic titration are normal.20 Dysregulation of inflammatory substances is also evoked as the potential cause of FMF attacks, and special attention has been directed to hydroxy-fatty acids. Using chromatography techniques, Aisen et aP” showed that patients with FMF have high serum levels of 5-hydroxicosatetraenoic acid (a major product of the 5-lypoxygenase pathway by which leukotrienes are formed) and 9- and 13-hydroxycosatetraenoic acids. These hydroxy-fatty acids have the capacity to stimulate neutrophil aggregation and facilitate the liberation of lysosomal enzymes. The circulation of lypoxygenase products may be a marker of an enzymatic defect leading to the abnormal formation or elimination of oxidized fatty acids. Immune regulation in FMF has been studied and in some cases has been shown to be abnormal. An imbalance between T cells and natural killer cells has been reported.27,31 The participation of other cytokines such as tumor necrosis factor appears unimportant in the pathogenesis of the disease.32 Levels of some acute-phase reactant glycoproteins such as hap-

147

toglobin and cu2-macroglobulin apparently are elevated.20 In spite of the evidence of immunologic abnormalities in this disease, FMF is not considered a primary autoimmune or connective tissue disease. In a recent study,33 the presence of autoantibodies to double-stranded DNA, using enzyme-linked immunosorbent assay and nitrocellulose filter assay, showed no difference between serum from patients with FMF and that from healthy controls. The same lack of positivity was noted when Western blotting with HeLa cells was used to detect anti-Sm, RNP, SSA/Ro, and SSB/La in patients with FMF. The most attractive hypothesis regarding the etiology of FMF is the recent postulation of Shohat et allo concerning a lipocortin deficiency in FMF patients. Combining most of the abnormalities reported and an autosomal recessive inheritance pattern, these investigators suggest that there is an absence of lipocortin or a dysfunctional molecule in patients with FMF. Lipocortins are a family of proteins synthesized in the nucleus under the influence of cortisol acting on its membrane receptor. The absence of these proteins is possible only by the homozygous expression of a mutant allele or alleles lacking a normal gene product. This pattern is consistent with an autosomal recessive condition. The lipocortins have the ability of inhibit phospholipase AZ, the main enzyme that converts phospholipids into arachidonic acid. Phospholipase A2 can be activated by cyclic adenosine monophosphate in the presence of calcium. Any stimuli that may be able to increase the activity of adenyl cyclase (such as catecholamine release, stress) in the absence of the inhibitory mechanism of lipocortins can produce an attack of fever, pain, and inflammation. This phenomenon is a potential explanation for the wellknown absence of response to steroid therapy in these patients. Treatment

Treatment, prophylactic prevention of acute attacks, and long-term outcome have evolved since the suggestion by Goldfinger in 197234that daily colchicine administration may prevent the febrile attack of FMF. Before Goldfinger’s study there was no specific and successful treatment for these patients. A multitude of scientific and

148

nonscientific treatments such as antibiotics, vitamins, antihistamines, antimalarials, salicylates, steroids, and elimination diets were tried without success.6 In 1983, Peters et al35 reported their experience with 85 patients who received colchicine in an average dose of 1.2 to 1.8 mg/d for at least 3 years. Twenty-three patients did not complete the treatment for different reasons: 3 discontinued because of side effects (diarrhea, decreased libido), 8 did not comply with the regimen, and in 12 the disease did not respond to colchicine. The frequency and severity of attacks of fever and pain in the remaining 62 patients were decreased. In all, 39 patients ceased to have attacks for the period of the study, 22 had only one to four attacks a year, and only 1 had five to six attacks a year. This frequency is in sharp contrast to the number of attacks occurring before therapy, which was more than 12 a year in more than half of patients. According to the experience of Pras et al5 in more than 1,100 patients, symptoms of pain are dramatically relieved in about 75% of the patients from the moment they start taking the drug. The rest experience attacks, but they are less frequent, shorter in duration, and milder in intensity. The recommended dose is 1 to 2 mg/d; most patients who do not respond to 2 mg/d will not respond to higher doses. The side effects of colchicine are mild and transient, mainly diarrhea, nausea, and mild rash. Although colchicine is very effective in decreasing the frequency and intensity of attacks, it is not as good in aborting the attack once it has started. Of 20 patients who started taking 0.6 mg of colchicine every hour for no more than 5 hours at the onset of the attack, only 6 reported relief of pain. The 14 other patients reported no effect from this drug regimen.6 During the acute attack, ordinary NSAIDs are the medication of choice. Narcotic analgesics must be prescribed cautiously because FMF is a chronic disease and the continuous administration of narcotics can produce physical and psychological dependance. Recently, Ben-Chetrit and Levy36 reported their long-term experience with colchicine after 15 years or more of treatment. Their findings are similar to those of previous reports regarding the utility of this drug in decreasing the frequency and intensity of the attacks associ-

GARCIA-GONZALEZ

AND WEISMAN

ated with only mild adverse effects. The importance of this report is that colchicine was administered to pregnant women and children. Eleven women took the drug during their pregnancies and delivered 15 normal babies. The youngest patient taking colchicine was 4 years old, and the follow-up of the development of 7 children did not show growth retardation. Safety in childhood and pregnancy is suggested but not established by this report. One of the most striking observations regarding the utility of colchicine in the prevention and treatment of the amyloidosis of FMF was observed in 1986. Zemer et a13’ studied 960 patients without proteinuria and 110 FMF patients with proteinuria at the moment they started taking the drug. After a long-term follow-up of at least 8 years, they noted that only 1.7% of the compliant patients developed proteinuria. These data are in contrast with the frequency of proteinuria reported in previous series (26%) in which colchicine was not administered. Among the 86 patients who had proteinuria but not the nephrotic syndrome, proteinuria resolved in 5, stabilized in 68, and deteriorated in 13. Progression to end-stage renal failure was the rule in the 24 patients in whom proteinuria was in the nephrotic range when they began taking colchicine. This last observation has been made by others5 although there is a case report from Denmark38 of a 12-year-old girl with FMF and progressive renal insufficiency who began taking colchicine and, after 7 months, had a gradual decrease in serum creatinine concentration. The mechanism of action of colchicine in FMF has been the subject of much speculation. It has been demonstrated in vitro that colchicine interferes with microtubule formation, degranulation of neutrophils, and alteration of leukocyte adenosine 3’,5’-cyclic phosphate levels.39 Shohat et al”’ suggest that colchicine, which reduces chemotaxis of granulocytes and therefore prevents further secretion of inflammatory mediators, prevents FMF attacks by interfering with the amplification loop of end products of phospholipase A2 and its further phospholipase A2 activation on vicinity neutrophils. The results of synovectomy in the case reported herein have prompted us to reconsider this mode of therapy. The utility of synovectomy

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MEDITERRANEAN

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FEVER

in chronic inflammatory diseases in general is controversial; however, there appears to be general agreement concerning the short- to medium-term relief of pain and elimination of swelling in spite of the radiographic progression of the systemic disease and clinical deterioration (functional class) of the patient.40 This agreement is particularly true for rheumatoid arthritis, in which the synovium is the immunocompetent tissue and more widespread systemic immunologic abnormalities are present. It was evident in this case that after synovectomy the patient did not develop effusions and that arthralgias were greatly reduced in intensity and almost disappeared in that articulation for periods ranging from 3 to 10 years. There are no reports in the literature concerning the treatment of FMF arthritis with surgical extirpation of the synovium. FMF appears to be a localized process that affects different membranes surrounding peritoneal, synovial, and pleural cavities, and immune/ inflammatory alterations are mainly localized to these membranes. In addition, the major clinical manifestations of FMF arthritis are pain and swelling followed by complete recovery of the joint after the attack subsides. With the response of our patient, we speculate that synovectomy might be a useful option for patients with FMF arthritis that does not respond adequately to prophylactic therapy with colchicine or those in whom the attacks are so disabling that functional disability is a result. A prospective, controlled clinical study is needed to prove the value of this concept. We do not have an explanation for the occurrence of dramatic bone proliferation around the affected articulations in this patient. It is also possible that this patient has a form of juvenile polyarthritis; however, he is a Sephardie Jew with a family history of FMF who fulfills all of the major and two of three minor criteria of Sohar et al6 in addition to displaying high levels of SSA. The radiographs show that during the arthritis attack there was exuberant heterotopic bone proliferation. It is known that periostitis may be present in some acute and chronic inflammatory arthritides such as joint infections

and seronegative spondyloarthropathies in addition to different conditions such as neoplasms, vascular insufficiency, and various forms of hypertrophic osteoarthropathy.41 One of the more attractive theories about the pathogenesis of bone proliferation has been proposed by Martinez-Lavin,42 who postulates that in these patients there is an increase in production or decrease in elimination of one or several peptide products called growth factors, all acting by stimulating DNA synthesis and growth in target cells. The most likely growth factor involved in the genesis of periostitis is platelet-derived growth factor (PDGF). This macromolecule was initially encountered in the OLgranules of platelets, but it is now known that it can be produced by endothelium, newborn smooth muscle, fibroblasts, and placenta.43 During the acute attack of inflammation in FMF there may be increased vascular hyperplasia in synovial tissues and over periarticular structures, clinically evidenced by periarticular tenderness and muscle atrophy as well as by severe transient osteoporosis on radiographs. Vascular endothelium may be the synthetic source of this PDGF. We do not know why periostitis is not a more common manifestation in FMF. It is possible that in other cases the process is transient and sometimes reversible, and only patients studied prospectively would be observed to have these findings. In summary, we report a case of FMF in which the principal clinical manifestations are arthritis associated with periarthritis, and the dominant radiographic abnormality is periosteal new bone formation. The patient did not have an adequate response to oral administration of NSAIDs or to intraarticular application of corticosteroids, and there was no adequate response to the prophylactic use of colchicine. Synovectomy appeared to be an effective shortand medium-term treatment for pain and swelling in the present case. We do not have a satisfactory explanation for the presence of dramatic periarticular manifestations observed clinically and radiographically in this patient, but by analogy newly recognized growth factors such as PDGF may be involved.

REFERENCES 1. Heller H, Sohar E, Sherf L: Familial fever. Arch Intern Med 102:50-71,1958

Mediterranean

2. Heller H, Gafni familial Mediterranean

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