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Fibromyalgia syndrome in patients infected with human immunodeficiency virus
Fibromyalgia Syndrome in Patients Infected With Human Immunodeficiency Virus ROBERT W.SIMMS, M.D.,CRISTIANOA.F. ZERBINI, M.D., NOREENFERRANTE,M.D.,
JOHNANTHONY,B.S., DAVIDT.FELSON,M.D.,M.P.H., DONALDE. CRAVEN,M.D., ~~~~~~BOSTONCITYHOSPITALCLINICALAIDSTEAM*, Boston, Massachusetts
PURPOSE: To prospectively assess rheumatic manifestations of human immunodeficiency virus (HIV) disease in a municipal hospital clinic population in which intravenous drug use was the most common risk factor for HIV infection. PATIENTSANDMETHODS: Patientswithdocumented HIV infection were evaluated for rheumatic disease using a standardized questionnaire and examination. Patients with fibromyalgia were compared with HIV-infected patients without fibromyalgia and with fibromyalgia patients without known risk factors for HIV infection. RESULTS: Thirty-seven of 140 patients with HIV infection had muskuloskeletal symptoms. Three of these 37 patients had arthritis, but none had Reiter’s syndrome or psoriatic arthritis. Thirty (81%) of 37 patients had chronic musculoskeletal symptoms (for 3 months or longer). Twenty of 30 patients with chronic musculoskeletal symptoms had polyarthralgia, and of those, 15 (75%) were found to have either definite or probable fibromyalgia syndrome. Therefore, fibromyalgia syndrome was found in 41% of HIVinfected patients with musculoskeletal symptoms and in approximately 11% of all HIV-infected patients. Fibromyalgia patients with HIV infection had a longer duration of HIV infection (p = 0.01) and more frequently reported past depressed mood (p = 0.001) than HIV-infected patients without fibromyalgia. Compared with 301 patients with fibromyalgia syndrome and no *John Chen. M.D., Sheila E. Chapman, M.D., Timothy P. Cooley, M.D., Jon D. Fuller, M.D., Howard Libman, M.D.. Joan Lebow, M.D., Maura Fagan. M.D., Harrison W. Farber, M.D., Micheie Martin, R.N., Kathleen A. Steger, R.N., M.P.H., BethA. Zeeman. M.D. From the Arthritis Section (RWS, CAFZ, NF, JA, DTF) and the Clinical AIDS Program (DEC, JC. SEC, TPC. JDF, HL, JL, MF, HWF, MM, KAS, BAZ), Boston University School of Medicine, Department of Medicine and Thorndike Memorial Laboratories, Boston City Hospital, Boston, Massachusetts. This work was supported in part by Multipurpose Arthritis Center Grant AR20613from the National Institutes of Health and was presented in part at the 59th Annual Meeting of the American College of Rheumatology, Seattle, October 1990. Requests for reprints should be addressed to Robert W. Simms, M.D., Arthritis Center, Boston University School of Medicine, 71 East Concord Street, Boston, Massachusetts 02118. Manuscript submitted June 25, 1991, and accepted in revised form November 27, 1991.
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known risk behavior for HIV, known HIV-infected patients with fibromyalgia were more commonly male (p = 0.001) and reported current depressed mood more frequently (p = 0.0001). CONCLUSION: Few patients with arthritis were noted among HIV-infected patients who had intravenous drug use as risk behavior. By comparison, fibromyalgia syndrome appeared to be a common cause of musculoskeletal symptoms in this patient population.
ver the past several years, a number of studies 0nodeficiency have reported the association of human immuvirus type I (HIV) infection with arthralgia [ 11, Reiter’s syndrome [2], psoriatic arthritis [3,4], Sjbgren’s-like syndrome 15-71, polymyositis [&lo], vasculitis [11,12], nonspecific oligoarthritis [13], and most recently fibromyalgia syndrome [ 141. A variety of autoimmune phenomena have also been described in association with HIV infection [15]. Although HIV has been isolated from synovial fluid [16], and p24 core antigen has been detected in synovial membrane from several patients with HIV-associated arthritis [17], the pathogenesis of rheumatic conditions associated with HIV infection remains unknown. Rheumatic disorders may be the result of direct effects of HIV or an immune response to HIV infection or result from confounding factors, such as an increase in exposure to infectious agents known to be associated with reactive arthritis. Previous studies reporting the association between rheumatic disorders and HIV infection have been derived primarily from homosexual men, and little information is available from patients with intravenous drug use as a risk behavior. Furthermore, only one prior study of rheumatic disorders in HIV infection has systematically assessed patients for fibromyalgia [14], a musculoskeletal pain disorder of unknown cause that has been linked to depression [18] and possibly to chronic viral infection
PI.
In this study, we used a standardized questionnaire and clinical examination to characterize rheumatic manifestations of HIV infection in an inner-
FIBROMYALGIA
city patient population in whom intravenous drug use was the predominant risk behavior for the acquisition of HIV. Because the majority of HIV-infected patients with chronic arthralgia fulfilled diagnostic criteria for fibromyalgia syndrome, we compared this group with HIV-infected patients without fibromyalgia and with a group of patients with fibromyalgia and no known risk factors for HIV infection.
PATIENTS AND METHODS Study Patients With HIV Infection We conducted a prospective evaluation of rheumatic manifestations of HIV infection at the Boston City Hospital (BCH) Immunodeficiency Clinic. The BCH Immunodeficiency Clinic functions as the site of primary care for 348 inner-city patients with HIV infection. The clinic is comprised of 74% males, 60% minorities (30% American black, 8% Haitian, 18% Hispanic, 1% Asian, 3% other), and 55% have intravenous drug use as the sole risk behavior for acquisition of HIV infection. Eligible patients included all adult patients with HIV infection documented by enzyme-linked immunoabsorbant assay and confirmed by Western blot, who were referred to the study team for evaluation of musculoskeletal symptoms by their primary care physicians. Patients were also required to speak English or to have a translator present at the time of evaluation. The study was approved by the Institutional Review Board of BCH; all study participants gave written, informed consent. The study was conducted during two of five BCH Immunodeficiency Clinics with a total of 140 patients followed, and these two clinics were canvassed thoroughly to identify those patients with musculoskeletal symptoms, who were then specifically referred to the study team. Although the focus of the study was on those with musculoskeletal symptoms, a smaller group of patients without musculoskeletal symptoms was also evaluated. Patients attending the two clinics that were canvassed did not differ either in demographic characteristics or in manifestations of HIV infection from the entire group of patients attending the BCH Immunodeficiency Clinic. Patients with symptoms or a diagnosis of a musculoskeletal disorder that preceded the diagnosis of HIV infection by 24 months or greater were excluded from the analysis. The 24-month figure was derived from the data of Winchester et al [2], in which Reiter’s syndrome was reported to occur up to 12 months prior to the diagnosis of HIV infection. The time period was extended to increase our yield of potential patients with HIV-associated rheumatic disorders. HIV disease was staged according to accepted Centers for Disease Control criteria [20],
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antiviral medications used to treat HIV infection, such as zidovudine (ZDU, formerly azidothymidine or AZT) and 2’,3’ dideoxyinosine (dd1) were documented. CD4 (helper or inducer) T-lymphocyte counts from peripheral blood were counted with the use of monoclonal antibodies and flow cytometry, and counts were obtained within 3 months of the musculoskeletal examination. HIV-infected patients entering the study completed a detailed, rheumatologist-administered questionnaire and standardized musculoskeletal examination, including joint and tender point examination. The questionnaire included data on demographics, risk factors for HIV infection, HIV disease manifestations, and rheumatic symptoms. Patients were specifically asked about the presence or absence of pain at 16 joint sites (hands, wrists, elbows, shoulders, hips, knees, ankles, feet) bilaterally, the duration of these symptoms, and the temporal association with HIV diagnosis and disease manifestations. Patients were also queried about the presence of myalgia, myalgia location (upper extremity, lower extremity, cervical spine, thoracic spine, lumbar spine), myalgia chronology, symptoms of fatigue, and sleep disturbance. Definition of Terms Musculoskeletal symptoms present for less than 3 months were defined as acute or subacute; symptoms present for greater than or equal to 3 months were defined as chronic. The diagnoses of Reiter’s syndrome and psoriatic arthritis were defined by previously proposed criteria [21,22]. To determine self-reported depressed mood, patients were specifically asked if they were currently or had in the past been depressed, “down in the dumps,” or “blue”. An affirmative response to any one of these three questions was interpreted to indicate depressed mood. Current depressed mood was defined as depressed mood occurring at the time of evaluation. Past depressed mood was defined as depressed mood occurring prior to the diagnosis of HIV infection. Tender point sites assessed on examination included (1) occiput: bilateral at suboccipital muscle insertion; (2) low cervical: bilateral at the anterior aspects of the intertransverse spaces at C5-C7; (3) trapezius: bilateral, at midpoint of the upper border; (4) supraspinatus: bilateral, at origins, above the scapula spine near the medial border; (5) second rib: bilateral, at the second costochondral junction, just lateral to the junctions on upper surfaces; (6) lateral epicondyle: bilateral, 2 cm distal to the epicondyles; (7) gluteak bilateral, in upper outer quadrants of buttocks in anterior fold of muscle; (8) greater trochanter: bilateral, posterior to trochanApril
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tions, or medication used to treat HIV infection and its complications. Depressed mood was assessed in a similar manner to that described above: patients were specifically asked if they were currently or had in the past been depressed, but were not routinely asked if they were “down in the dumps” or “blue.” Past depressed mood in this group was defined as that which occurred before symptoms of fibromyalgia syndrome developed. Musculoskeletal examination and tender point examination were performed, and the results were recorded in an identical fashion to that described above, with the exception that tender points were graded as: 0 = not tender, l+ = slightly tender, and 2+ = markedly tender. For the purposes of analysis, tender points graded l+ or 2+ were reclassified as “positive.”
MUSCULOSXELETAL SYMPTOMS
I
I
FIBROMYALGIA SMDROME (N-1 5)
NO DIAGNOSTIC I
Figure 1. Flow chart describing tations in patients with human infection.
principal rheumatic manifesimmunodeficiency virus (HIV)
teric prominence and (9) knee: bilateral, at the medial fat pad proximal to joint line. A tender point was considered “positive” if a patient stated that its palpation was painful [23]. Definite fibromyalgia syndrome was defined using the American College of Rheumatology (ACR) 1990 criteria [23]: (1) presence of widespread musculoskeletal pain of at least 3 months’ duration and (2) at least 11 of 18 possible tender points by digital palpation. Patients having the first of these latter criteria, but with between eight and 10 of 18 possible tender points were considered to have probable fibromyalgia syndrome. Fatigue was considered present if patients were reported feeling “exhausted frequently or all the time.” Sleep disturbance was considered present if patients reported “frequent awakening, ” “difficulty getting to sleep,” or “awakening too early.” Patients Without Known Risk Factors for HIV Infection Patients with HIV infection and definite or probable fibromyalgia were compared with a large population of fibromyalgia patients without known risk factors for HIV infection who were evaluated prospectively from 1984 to 1989 in an academic rheumatology practice. The demographic features of this population have been previously described [24]. All patients completed a detailed rheumatologist-administered questionnaire that differed from the questionnaire utilized with HIV-infected subjects only in that it did not specifically assess risk factors for HIV infection, HIV disease manifesta370
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Statistical Analysis Statistical significance was assessed using the Fischer’s exact and chi-square test for categorical variables, and Student’s t-test for continuous variables. Because we compared fibromyalgia patients with or without HIV infection on a large number of variables, we lowered the (L level considered significant to 0.01 (two sided).
RESULTS HIV-Infected Patients With Musculoskeletal Symptoms Sixty-six HIV-infected patients were evaluated; 21 had no musculoskeletal symptoms (Figure 1). Of the 45 HIV-infected patients with musculoskeletal symptoms, eight were excluded due to the presence of a known prior rheumatic disorder or musculoskeletal symptoms that preceded HIV infection: systemic lupus erythematosus (one), rheumatoid arthritis (one), posttraumatic osteoarthritis (two), mechanical knee derangement following trauma (three), and fibromyalgia (one). Twenty-one (56%) of the 37 patients with musculoskeletal symptoms had arthralgia, 16 (43%) had arthralgia and myalgia, and one patient had myalgia only. These patients were predominantly white, male, and had intravenous drug use as the principal risk behavior for HIV infection (Table I). The higher proportion of white patients in the study group compared with the overall BCH Immunodeficiency Clinic population may reflect differing attitudes about participation in clinical research. Of note is that most of the patients had AIDS and had a mean CD4 count of 215/mm3. Patients With Chronic Musculoskeletal Symptoms Thirty (81%) of the 37 study patients (81%) had chronic musculoskeletal symptoms (Table II). Twenty (67%) of 30 patients had polyarticular
FIBROMYALGIA
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TABLE I
TABLE II
Characteristicsof 37 Patients With Human lmmunodeficiency Virus [HIV) infection and MusculoskeletalSymptoms
MusculoskeletalExamination in 37 Patients With Human lmmunodeficiencyVirus (HIV) Infection and Musculoskeletal Symptoms
Mean age(y)
38 + 7.2*
Sex Males Females
Po;“hr$ia
Arthralgia Olig~~h;lgia
MoytJh;lgia
Symptoms Chronic (n = 30) Fibromyalgia Oligoarthritis Tendonitisl bursitis No diagnostic findings
Ra;ietmhnic group 22 (60) Black Hispanic Oriental
‘i IF 1 (2)
Risk behavior for HIV Intravenous drug user (IVDU) Homosexual only Sex partner of IVDU IVDU and homosexual Otheri
Acute/subacute (n = 7) Polyarthritis Tendonitisi bursitis No diagnostic findings
Clinical HIV disease Asymptomatic Symptomatic (not AIDS) AIDS Mean duration of HIV seropositivity
ET AL
15120 216 2% 5120
416
214
112 -
113
-
112
213
212
2 IV 22 (60) (mo)
Mean CD4 lymphocyte count/mm3
28.2 + 24 215 + 170
Antiretroviral therapy Zidovudine Dideoxyinosine lean + standard deviation. lo. I%). ransfusion-acquired (one); no identified risk behavior (three).
symptoms, and of these, 15 (75%) had definite or probable fibromyalgia syndrome. Of the 15 patients with fibromyalgia syndrome, seven had greater than 11 of 18 tender points, and eight had between 8 and 10 tender points. Two homosexual men had arthritis: one with an asymmetric, lower extremity oligoarthritis and the other with oligoarthritis associated with Achilles tendonitis. Two other homosexual men had tendonitis or bursitis, but no other musculoskeletal manifestations. Thus, all four patients with chronic musculoskeletal symptoms and either arthritis, tendonitis, or bursitis had homosexuality as a risk behavior for HIV infection. Patients With Acute or Subacute Symptoms Seven patients had acute or subacute joints symptoms. Two of these seven patients had polyartitular complaints, and one patient had multiple tender points, but no evidence of synovitis and a clinical picture consistent with fibromyalgia syndrome, although this patient did not meet diagnostic criteria due to the short duration of symptoms. One additional patient (with intravenous drug use as a risk factor) had an acute polyarthritis involving the small joints of hands and feet. Extensive evaluation of this patient failed to reveal a cause, and the
patient’s joint complaints and findings eventually resolved completely after 6 weeks. No patients in this study were found by history or physical examination to have evidence of myopathy, although creatine phosphokinase levels were not routinely measured. Comparison of HIV-Infected Patients With and Without Fibromyalgia Fifteen HIV-infected patients with fibromyalgia were compared to 43 without fibromyalgia. The latter group was comprised of 22 patients without fibromyalgia and 21 patients with no musculoskeletal symptoms (Table III). Patients with fibromyalgia were more likely to have a longer mean duration of HIV infection (p = 0.01) and to have past depressed mood (p = 0.001) than patients without fibromyalgia. Two other differences not reaching our significance level of 0.01 included the tendency of fibromyalgia patients with HIV infection to be female and to have a high rate of current depressed mood. The two groups did not differ with respect to mean age, HIV risk group, extent of HIV disease, use of antiviral therapy, mean CD4 count, or extent of HIV disease. There was no correlation between CD4 count and the proportion of patients with or without fibromyalgia with CD4 counts 200 cells/mm3, 200 to 400 cells/mm3, or greater than 400 cells/mm3. Comparison of HIV-Infected Fibromyalgia Patients With Fibromyalgia Patients Without Known Risk Behavior for HIV-Infection The 15 HIV-infected patients with fibromyalgia were significantly more likely to be male (p = O.OOl), had a shorter duration of musculoskeletal April
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TABLE IV
TABLE III Comparisonof Patients With Human lmmunodeficiencyVirus (HIV) Infection and Fibromyalgia to HIV-Infected Patients Without Fibromyalgia
Sex Male Female
9 (60) 3 (20)
Homosexual male of HIVseropositivity
HIV disease Asymptomatic Symptomatic (not AIDS) AIDS Antiretroviral therapy Zidovudine Dedoxyinosine
l! :::,I
9 (60)
0.40 O.Ol§
‘E I:!;
21 (49)
“2 IL’
i: IKP’
33 (77) 5 (11)
0.53 0.78
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268(89) 0.85
Presence of sleep disturbance
12 (80)
257(86) 0.37
Self-reported depressed mood Current Past
5 IKP’
97 (32) 0.00011 122(41) 0.23
7115 (47)
209/301
(69)
0.23
,,...
0.06 0.001~
The low prevalence of arthritis among patients with musculoskeletal symptoms in our study contrasts with other studies of HIV-infected homosexual men that have reported rates of Reiter’s syndrome between 5% and 10% [1,25], perhaps reflecting the high proportion of patients with intravenous drug use as a risk behavior. Berman and co-workers [l] reported arthralgia in 45%, most of whom were homosexual men; unfortunately, fibromyalgia was not assessed. The low rate of true articular disease in our study suggests that the occurence of Reiter’s syndrome or oligoarthritis in patients with HIV infection may be associated with other infectious agents transmitted between homosexual men [26,27]. A significant proportion of our patients complained of myalgias, although most had arthralgias as well. Polymyositis associated with HIV infection and long-term zidovudine therapy may cause myalgia, weakness, and elevated serum creatine kinase levels [S-10,23]. Although we did not routinely measure serum creatine kinase levels, we found no cases of concomitant myopathy and found no difference in the frequency of fibromyalgia in patients treated with zidovudine. Nevertheless, future studies of fibromyalgia in this population should probably include measurements of creatine kinase to fully exclude low-level myopathy. Of the 20 patients with HIV infection and chronic musculoskeletal symptoms in our study, 75% had
The overall rate of arthritis was low in our patient population; two patients had oligoarthritis and none had Reiter’s syndrome or psoriatic arthritis. The American
0.0021
14(93)
..
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1992
65 2 70
0.001*
*Mean * sranaaro aevlauon. tNo. (%I. tp SO.01.
symptoms (p = 0.002), and more commonly reported current, depressed mood (p = 0.0001) than did the 301 patients with fibromyalgia and no known risk factors for HIV infection (Table IV). No significant differences were noted between the two groups in the proportion of patients with symptoms characteristic of fibromyalgia syndrome, such as fatigue, sleep disturbance, and the presence of multiple tender points. The high predominance of males probably reflects the HIV patient population. The decreased duration of musculoskeletal symptoms may have been due to the exclusion of patients in the HIV-infected group with symptoms greater than 24 months prior to HIV serodiagnosis, differences in referral patterns, and the fact that most patients followed in the HIV clinic had been followed for a short period of time, or may reflect the overall high mortality rate associated with HIV infection. The increased rate of current self-reported depressed mood may be related to the patients’ HIV infection or intravenous drug use.
April
26 rt 24
34 (11) 267(89)
due 0.10
Presence of fatigue
Proportion with multiple tender points(zll/lB)
*Mean i standard deviation. tNo. (%I. $Riskfactonotherthan intravenousdruguse WDU) and homosexualnot listed. *p SO.01.
372
7 (47)+ 8 (53)
Mean duration of musculoskeletal symptoms (mo)
249 f 184 206+ 164 0.46
depressed mood
Past
22.1 i: 14.7
Sex Male Female
0.73
l: iFP’
CD4 lymphocyte count/mm3 Se;lfgted
33.7 i: 14.3
ii 1%
37.5 + 7.6* 42.9i: 10.2
Mean age (y)
0.03 :?I I:;;
factort
Me;n$ration m
Fibromyalgia Without Known With HIV HIV Risk Infection Factors (tl = 15) (n = 301)
37.5 i 7.6* 37.0f 6.5 0.81
Mean age(y)
HI:;;
Comparisonof Fibromyalgia Patients With HIV Infection to Fibromyalgia Patients Without Known HIV Risk Factors
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definite or probable fibromyalgia syndrome. Based on a denominator of 140 patients, we estimate a prevalence of fibromyalgia syndrome of approximately 11% in this population of patients with HIV infection. The finding of an association between fibromyalgia and HIV infection in our series confirms Buskila’s studies in homosexual men [14], in which approximately 20% of patients met the Smythe criteria for fibromyalgia [14]. The Smythe criteria differ somewhat from the American College of Rheumatology (ACR) criteria [20] utilized in this study in that only tenderness on tender point examination is required rather than specific symptoms. As a result, the Smythe criteria may overestimate the true prevalence of fibromyalgia syndrome. We found that eight patients with HIV infection and chronic musculoskeletal symptoms had between eight and 10 tender points-less than the 11 required by the ACR criteria. While these patients were considered to have probable fibromyalgia, it is possible that this was an incorrect diagnosis. We consider this unlikely, however, since using eight tender points as the minimum number required for the diagnosis in combination with the symptom criterion of widespread pain still has high sensitivity and specificity for diagnosis [20]. It is possible that intravenous drug use may confound the association of fibromyalgia with HIV infection, even though a recent review of the rheumatic manifestations of substance abuse did not include fibromyalgia syndrome [29]. Nevertheless, a prospective assessment of fibromyalgia in HIV-seronegative intravenous drug users should be studied to exclude this possibility. The association with fibromyalgia syndrome and HIV infection may also be related to depression. A lifetime history of major depression has been reported in as many as 50% to 70% of patients with fibromyalgia syndrome [18,30,31]. In most of these patients, a history of major depression preceded symptoms attributable to fibromyalgia syndrome, and most patients were not found to have major depression at the time that fibromyalgia was diagnosed [18,30,31]. A recent study has also found that the central clinical features of fibromyalgia syndrome, such as the number of pain sites, tender points, fatigue, and poor sleep, were independent of psychologic status [32]. Unfortunately, relatively little is known about the prevalence of depression in the setting of HIV infection, particularly in HIVinfected patients with intravenous drug use as a risk factor, but it is likely to be highly prevalent. Our data indicate that current, self-reported depressed mood, while more common in HIV-infected fibromyalgia patients compared to those without known risk factors for HIV infection, was not significantly different in frequency from non-fibromyal-
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gia, HIV-infected patients. These data suggest that current, self-reported depressed mood is the result of HIV infection. Past self-reported depressed mood seemed to be significantly more frequent in those HIV-infected patients with fibromyalgia compared to those without fibromyalgia, but not significantly different in frequency when fibromyalgia patients with HIV infection were compared to those without known risk factors for HIV infection. This seems to indicate that prior depression as a risk factor for fibromyalgia is operating in patients with and without HIV infection. One limitation of our observations with respect to depression is that we used self-reported depressed mood and not a validated depression inventory in all patients. Therefore, our results should be viewed as preliminary until depression can be assessed in this population using a validated depression inventory. Such an inventory will need to control for symptoms of HIV infection (weight loss, fatigue, etc.), and fibromyalgia (somatic pain and fatigue) that confound the assessment of depression using many conventional inventories. Chronic infection is another possible explanation for the association of fibromyalgia syndrome and HIV infection. Both fibromyalgia syndrome and chronic fatigue syndrome have been associated with chronic viral infection [19,33,34]. Preliminary reports have linked human herpes virus type 6 [35,36], parvovirus B19 infection [37], and Coxsackie B2 infection [38] to these syndromes. There has also been an association of parvovirus B19 and hematologic complications of HIV infection [39]. Recent reports have also linked fibromyalgia syndrome to Lyme disease [40,41]. Therefore, chronic HIV infection may be a risk factor for fibromyalgia syndrome. In summary, fibromyalgia syndrome was a common cause of chronic musculoskeletal symptoms in our patients with HIV infection. Identification of fibromyalgia syndrome in these patients coupled with appropriate treatment may improve their quality of life and avoid unnecessary diagnostic and therapeutic interventions. Furthermore, the association of HIV infection and fibromyalgia syndrome may provide an important opportunity to further study the association of depression and chronic viral infection in this common rheumatic disorder.
ACKNOWLEDGMENT We are grateful to Dr. Don L. Goldenberg
for reviewing
the manuscript.
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22. Kammer GM, Soter NA, Gibson DJ, Schur PH. Psoriatic arthritis: a clinical immunologic and HLA study of 100 patients. Semin Arthritis Rheum 1979; 9: 75-97. 23. Wolfe F, Smythe HA, Yunus M, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum 1990; 33: 160-72. 24. Triadafilopoulos G, Simms RW, Goldenberg DL. Bowel dysfunction in fibromyalgia. Dig Dis Sci 1990; 36: 59-64. 25. Winchester R, Brancato L, ltescu S, Skovron ML, Solomon G. implications from the occurrence of Reiter’s syndrome and related disorders in association with advanced HIV infection. Stand J Rheumatol 1988; (Suppl) 74: 89-93. 26. Clark M, Kinsolving M. Chernoff D. The prevalence of arthritis in two HIVInfected cohorts [abstract]. Arthritis Rheum 1989; 32: S85. 27. Hochberg MC, Fox R, Nelson KR. Reiter’s syndrome is not associated with HIV infection [abstract]. Arthritis Rheum 1989; 33: 175. 28. Dalakas MC, llla I, Pezeshkpour GH, Lankaitis JP, Cohen B, Giffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990; 322: 1098-105. 29. Lohr KM. Rheumatic manifestations of diseases associated with substance abuse. Semin Arthritis Rheum 1987; 17: 90-l 11. 30. Hudson JI. Hudson MS, Pliner LF, Goldenberg DL. Pope HG. Fibromyalgia and major affective disorder: a controlled phenomenology and family history study. Am J Psychiatry 1985; 142: 441-6. 31. Goldenberg DL. Psychiatric and psychologic aspects of fibromyalgia syndrome. Rheum Dis Clin 1989; 15: 106-14. 32. Yunis M, Ahles TA, Aldag JC, Masi AT. Relationship of clinical features with psychological status in primaryfibromyalgia. Arthritis Rheum 1991; 34: 15-21. 33. Buchwald D, Goldenberg DL. Sullivan JL, Komoroff AL. The “chronic, active Epstein-Barr virus infection” syndrome and primary fibromyalgia. Arthritis Rheum 1987; 30: 1132-6. 34. Goldenberg DL, Simms RW. Geiger A, Komoroff A. High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice. Arthritis Rheum 1990; 33: 381-7. 35. Buchwald D, Saxinger C, Goldenberg DL, Gallo RC, Komaroff AL. Primary fibromyalgia (fibrositis) and human herpes virus-6: a serologic association [abstract]. Clin Res 1988; 36: 332A. 36. Komaroff AL, Saxinger C, Buchwald K, Geiger A, Gallo RC. A chronic “postviral” fatigue syndrome with neurologic features: serologic association with human herpes virus-6 [abstract]. Clin Res 1988; 36: 743A. 37. Naides SJ, Leventhal LJ. Freundlich 8. Fibromyalgia and parvovirus infection Arthritis Rheum 1991; 34: 1318-24. 38. Nash P, Chard M, Hazelman B. Chronic coxsackie B infection mimicking primary fibromyalgia. J Rheumatol 1989; 16: 1506-8. 39. Frickhofen N, Abkowitz JL, Safford M. et a/. Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-l): a treateable cause of anemia in AIDS. Ann intern Med 1990; 113: 926-33. 40. Sigal L. Summary of the first 100 patients seen at a Lyme disease referral center. Am J Med 1990; 88: 577-81. 41. Dinerman H, Steere AC. Fibromyalgia following Lyme disease: association with neurologic involvement and lack of response to antibiotic therapy [abstract]. Arthritis Rheum 1990; 33: S136.
JOHNANTHONY,B.S., DAVIDT.FELSON,M.D.,M.P.H., DONALDE. CRAVEN,M.D., ~~~~~~BOSTONCITYHOSPITALCLINICALAIDSTEAM*, Boston, Massachusetts
PURPOSE: To prospectively assess rheumatic manifestations of human immunodeficiency virus (HIV) disease in a municipal hospital clinic population in which intravenous drug use was the most common risk factor for HIV infection. PATIENTSANDMETHODS: Patientswithdocumented HIV infection were evaluated for rheumatic disease using a standardized questionnaire and examination. Patients with fibromyalgia were compared with HIV-infected patients without fibromyalgia and with fibromyalgia patients without known risk factors for HIV infection. RESULTS: Thirty-seven of 140 patients with HIV infection had muskuloskeletal symptoms. Three of these 37 patients had arthritis, but none had Reiter’s syndrome or psoriatic arthritis. Thirty (81%) of 37 patients had chronic musculoskeletal symptoms (for 3 months or longer). Twenty of 30 patients with chronic musculoskeletal symptoms had polyarthralgia, and of those, 15 (75%) were found to have either definite or probable fibromyalgia syndrome. Therefore, fibromyalgia syndrome was found in 41% of HIVinfected patients with musculoskeletal symptoms and in approximately 11% of all HIV-infected patients. Fibromyalgia patients with HIV infection had a longer duration of HIV infection (p = 0.01) and more frequently reported past depressed mood (p = 0.001) than HIV-infected patients without fibromyalgia. Compared with 301 patients with fibromyalgia syndrome and no *John Chen. M.D., Sheila E. Chapman, M.D., Timothy P. Cooley, M.D., Jon D. Fuller, M.D., Howard Libman, M.D.. Joan Lebow, M.D., Maura Fagan. M.D., Harrison W. Farber, M.D., Micheie Martin, R.N., Kathleen A. Steger, R.N., M.P.H., BethA. Zeeman. M.D. From the Arthritis Section (RWS, CAFZ, NF, JA, DTF) and the Clinical AIDS Program (DEC, JC. SEC, TPC. JDF, HL, JL, MF, HWF, MM, KAS, BAZ), Boston University School of Medicine, Department of Medicine and Thorndike Memorial Laboratories, Boston City Hospital, Boston, Massachusetts. This work was supported in part by Multipurpose Arthritis Center Grant AR20613from the National Institutes of Health and was presented in part at the 59th Annual Meeting of the American College of Rheumatology, Seattle, October 1990. Requests for reprints should be addressed to Robert W. Simms, M.D., Arthritis Center, Boston University School of Medicine, 71 East Concord Street, Boston, Massachusetts 02118. Manuscript submitted June 25, 1991, and accepted in revised form November 27, 1991.
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known risk behavior for HIV, known HIV-infected patients with fibromyalgia were more commonly male (p = 0.001) and reported current depressed mood more frequently (p = 0.0001). CONCLUSION: Few patients with arthritis were noted among HIV-infected patients who had intravenous drug use as risk behavior. By comparison, fibromyalgia syndrome appeared to be a common cause of musculoskeletal symptoms in this patient population.
ver the past several years, a number of studies 0nodeficiency have reported the association of human immuvirus type I (HIV) infection with arthralgia [ 11, Reiter’s syndrome [2], psoriatic arthritis [3,4], Sjbgren’s-like syndrome 15-71, polymyositis [&lo], vasculitis [11,12], nonspecific oligoarthritis [13], and most recently fibromyalgia syndrome [ 141. A variety of autoimmune phenomena have also been described in association with HIV infection [15]. Although HIV has been isolated from synovial fluid [16], and p24 core antigen has been detected in synovial membrane from several patients with HIV-associated arthritis [17], the pathogenesis of rheumatic conditions associated with HIV infection remains unknown. Rheumatic disorders may be the result of direct effects of HIV or an immune response to HIV infection or result from confounding factors, such as an increase in exposure to infectious agents known to be associated with reactive arthritis. Previous studies reporting the association between rheumatic disorders and HIV infection have been derived primarily from homosexual men, and little information is available from patients with intravenous drug use as a risk behavior. Furthermore, only one prior study of rheumatic disorders in HIV infection has systematically assessed patients for fibromyalgia [14], a musculoskeletal pain disorder of unknown cause that has been linked to depression [18] and possibly to chronic viral infection
PI.
In this study, we used a standardized questionnaire and clinical examination to characterize rheumatic manifestations of HIV infection in an inner-
FIBROMYALGIA
city patient population in whom intravenous drug use was the predominant risk behavior for the acquisition of HIV. Because the majority of HIV-infected patients with chronic arthralgia fulfilled diagnostic criteria for fibromyalgia syndrome, we compared this group with HIV-infected patients without fibromyalgia and with a group of patients with fibromyalgia and no known risk factors for HIV infection.
PATIENTS AND METHODS Study Patients With HIV Infection We conducted a prospective evaluation of rheumatic manifestations of HIV infection at the Boston City Hospital (BCH) Immunodeficiency Clinic. The BCH Immunodeficiency Clinic functions as the site of primary care for 348 inner-city patients with HIV infection. The clinic is comprised of 74% males, 60% minorities (30% American black, 8% Haitian, 18% Hispanic, 1% Asian, 3% other), and 55% have intravenous drug use as the sole risk behavior for acquisition of HIV infection. Eligible patients included all adult patients with HIV infection documented by enzyme-linked immunoabsorbant assay and confirmed by Western blot, who were referred to the study team for evaluation of musculoskeletal symptoms by their primary care physicians. Patients were also required to speak English or to have a translator present at the time of evaluation. The study was approved by the Institutional Review Board of BCH; all study participants gave written, informed consent. The study was conducted during two of five BCH Immunodeficiency Clinics with a total of 140 patients followed, and these two clinics were canvassed thoroughly to identify those patients with musculoskeletal symptoms, who were then specifically referred to the study team. Although the focus of the study was on those with musculoskeletal symptoms, a smaller group of patients without musculoskeletal symptoms was also evaluated. Patients attending the two clinics that were canvassed did not differ either in demographic characteristics or in manifestations of HIV infection from the entire group of patients attending the BCH Immunodeficiency Clinic. Patients with symptoms or a diagnosis of a musculoskeletal disorder that preceded the diagnosis of HIV infection by 24 months or greater were excluded from the analysis. The 24-month figure was derived from the data of Winchester et al [2], in which Reiter’s syndrome was reported to occur up to 12 months prior to the diagnosis of HIV infection. The time period was extended to increase our yield of potential patients with HIV-associated rheumatic disorders. HIV disease was staged according to accepted Centers for Disease Control criteria [20],
SYNDROME
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ET AL
antiviral medications used to treat HIV infection, such as zidovudine (ZDU, formerly azidothymidine or AZT) and 2’,3’ dideoxyinosine (dd1) were documented. CD4 (helper or inducer) T-lymphocyte counts from peripheral blood were counted with the use of monoclonal antibodies and flow cytometry, and counts were obtained within 3 months of the musculoskeletal examination. HIV-infected patients entering the study completed a detailed, rheumatologist-administered questionnaire and standardized musculoskeletal examination, including joint and tender point examination. The questionnaire included data on demographics, risk factors for HIV infection, HIV disease manifestations, and rheumatic symptoms. Patients were specifically asked about the presence or absence of pain at 16 joint sites (hands, wrists, elbows, shoulders, hips, knees, ankles, feet) bilaterally, the duration of these symptoms, and the temporal association with HIV diagnosis and disease manifestations. Patients were also queried about the presence of myalgia, myalgia location (upper extremity, lower extremity, cervical spine, thoracic spine, lumbar spine), myalgia chronology, symptoms of fatigue, and sleep disturbance. Definition of Terms Musculoskeletal symptoms present for less than 3 months were defined as acute or subacute; symptoms present for greater than or equal to 3 months were defined as chronic. The diagnoses of Reiter’s syndrome and psoriatic arthritis were defined by previously proposed criteria [21,22]. To determine self-reported depressed mood, patients were specifically asked if they were currently or had in the past been depressed, “down in the dumps,” or “blue”. An affirmative response to any one of these three questions was interpreted to indicate depressed mood. Current depressed mood was defined as depressed mood occurring at the time of evaluation. Past depressed mood was defined as depressed mood occurring prior to the diagnosis of HIV infection. Tender point sites assessed on examination included (1) occiput: bilateral at suboccipital muscle insertion; (2) low cervical: bilateral at the anterior aspects of the intertransverse spaces at C5-C7; (3) trapezius: bilateral, at midpoint of the upper border; (4) supraspinatus: bilateral, at origins, above the scapula spine near the medial border; (5) second rib: bilateral, at the second costochondral junction, just lateral to the junctions on upper surfaces; (6) lateral epicondyle: bilateral, 2 cm distal to the epicondyles; (7) gluteak bilateral, in upper outer quadrants of buttocks in anterior fold of muscle; (8) greater trochanter: bilateral, posterior to trochanApril
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tions, or medication used to treat HIV infection and its complications. Depressed mood was assessed in a similar manner to that described above: patients were specifically asked if they were currently or had in the past been depressed, but were not routinely asked if they were “down in the dumps” or “blue.” Past depressed mood in this group was defined as that which occurred before symptoms of fibromyalgia syndrome developed. Musculoskeletal examination and tender point examination were performed, and the results were recorded in an identical fashion to that described above, with the exception that tender points were graded as: 0 = not tender, l+ = slightly tender, and 2+ = markedly tender. For the purposes of analysis, tender points graded l+ or 2+ were reclassified as “positive.”
MUSCULOSXELETAL SYMPTOMS
I
I
FIBROMYALGIA SMDROME (N-1 5)
NO DIAGNOSTIC I
Figure 1. Flow chart describing tations in patients with human infection.
principal rheumatic manifesimmunodeficiency virus (HIV)
teric prominence and (9) knee: bilateral, at the medial fat pad proximal to joint line. A tender point was considered “positive” if a patient stated that its palpation was painful [23]. Definite fibromyalgia syndrome was defined using the American College of Rheumatology (ACR) 1990 criteria [23]: (1) presence of widespread musculoskeletal pain of at least 3 months’ duration and (2) at least 11 of 18 possible tender points by digital palpation. Patients having the first of these latter criteria, but with between eight and 10 of 18 possible tender points were considered to have probable fibromyalgia syndrome. Fatigue was considered present if patients were reported feeling “exhausted frequently or all the time.” Sleep disturbance was considered present if patients reported “frequent awakening, ” “difficulty getting to sleep,” or “awakening too early.” Patients Without Known Risk Factors for HIV Infection Patients with HIV infection and definite or probable fibromyalgia were compared with a large population of fibromyalgia patients without known risk factors for HIV infection who were evaluated prospectively from 1984 to 1989 in an academic rheumatology practice. The demographic features of this population have been previously described [24]. All patients completed a detailed rheumatologist-administered questionnaire that differed from the questionnaire utilized with HIV-infected subjects only in that it did not specifically assess risk factors for HIV infection, HIV disease manifesta370
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Statistical Analysis Statistical significance was assessed using the Fischer’s exact and chi-square test for categorical variables, and Student’s t-test for continuous variables. Because we compared fibromyalgia patients with or without HIV infection on a large number of variables, we lowered the (L level considered significant to 0.01 (two sided).
RESULTS HIV-Infected Patients With Musculoskeletal Symptoms Sixty-six HIV-infected patients were evaluated; 21 had no musculoskeletal symptoms (Figure 1). Of the 45 HIV-infected patients with musculoskeletal symptoms, eight were excluded due to the presence of a known prior rheumatic disorder or musculoskeletal symptoms that preceded HIV infection: systemic lupus erythematosus (one), rheumatoid arthritis (one), posttraumatic osteoarthritis (two), mechanical knee derangement following trauma (three), and fibromyalgia (one). Twenty-one (56%) of the 37 patients with musculoskeletal symptoms had arthralgia, 16 (43%) had arthralgia and myalgia, and one patient had myalgia only. These patients were predominantly white, male, and had intravenous drug use as the principal risk behavior for HIV infection (Table I). The higher proportion of white patients in the study group compared with the overall BCH Immunodeficiency Clinic population may reflect differing attitudes about participation in clinical research. Of note is that most of the patients had AIDS and had a mean CD4 count of 215/mm3. Patients With Chronic Musculoskeletal Symptoms Thirty (81%) of the 37 study patients (81%) had chronic musculoskeletal symptoms (Table II). Twenty (67%) of 30 patients had polyarticular
FIBROMYALGIA
SYNDROME
IN HIV INFECTION
/ SIMMS
TABLE I
TABLE II
Characteristicsof 37 Patients With Human lmmunodeficiency Virus [HIV) infection and MusculoskeletalSymptoms
MusculoskeletalExamination in 37 Patients With Human lmmunodeficiencyVirus (HIV) Infection and Musculoskeletal Symptoms
Mean age(y)
38 + 7.2*
Sex Males Females
Po;“hr$ia
Arthralgia Olig~~h;lgia
MoytJh;lgia
Symptoms Chronic (n = 30) Fibromyalgia Oligoarthritis Tendonitisl bursitis No diagnostic findings
Ra;ietmhnic group 22 (60) Black Hispanic Oriental
‘i IF 1 (2)
Risk behavior for HIV Intravenous drug user (IVDU) Homosexual only Sex partner of IVDU IVDU and homosexual Otheri
Acute/subacute (n = 7) Polyarthritis Tendonitisi bursitis No diagnostic findings
Clinical HIV disease Asymptomatic Symptomatic (not AIDS) AIDS Mean duration of HIV seropositivity
ET AL
15120 216 2% 5120
416
214
112 -
113
-
112
213
212
2 IV 22 (60) (mo)
Mean CD4 lymphocyte count/mm3
28.2 + 24 215 + 170
Antiretroviral therapy Zidovudine Dideoxyinosine lean + standard deviation. lo. I%). ransfusion-acquired (one); no identified risk behavior (three).
symptoms, and of these, 15 (75%) had definite or probable fibromyalgia syndrome. Of the 15 patients with fibromyalgia syndrome, seven had greater than 11 of 18 tender points, and eight had between 8 and 10 tender points. Two homosexual men had arthritis: one with an asymmetric, lower extremity oligoarthritis and the other with oligoarthritis associated with Achilles tendonitis. Two other homosexual men had tendonitis or bursitis, but no other musculoskeletal manifestations. Thus, all four patients with chronic musculoskeletal symptoms and either arthritis, tendonitis, or bursitis had homosexuality as a risk behavior for HIV infection. Patients With Acute or Subacute Symptoms Seven patients had acute or subacute joints symptoms. Two of these seven patients had polyartitular complaints, and one patient had multiple tender points, but no evidence of synovitis and a clinical picture consistent with fibromyalgia syndrome, although this patient did not meet diagnostic criteria due to the short duration of symptoms. One additional patient (with intravenous drug use as a risk factor) had an acute polyarthritis involving the small joints of hands and feet. Extensive evaluation of this patient failed to reveal a cause, and the
patient’s joint complaints and findings eventually resolved completely after 6 weeks. No patients in this study were found by history or physical examination to have evidence of myopathy, although creatine phosphokinase levels were not routinely measured. Comparison of HIV-Infected Patients With and Without Fibromyalgia Fifteen HIV-infected patients with fibromyalgia were compared to 43 without fibromyalgia. The latter group was comprised of 22 patients without fibromyalgia and 21 patients with no musculoskeletal symptoms (Table III). Patients with fibromyalgia were more likely to have a longer mean duration of HIV infection (p = 0.01) and to have past depressed mood (p = 0.001) than patients without fibromyalgia. Two other differences not reaching our significance level of 0.01 included the tendency of fibromyalgia patients with HIV infection to be female and to have a high rate of current depressed mood. The two groups did not differ with respect to mean age, HIV risk group, extent of HIV disease, use of antiviral therapy, mean CD4 count, or extent of HIV disease. There was no correlation between CD4 count and the proportion of patients with or without fibromyalgia with CD4 counts 200 cells/mm3, 200 to 400 cells/mm3, or greater than 400 cells/mm3. Comparison of HIV-Infected Fibromyalgia Patients With Fibromyalgia Patients Without Known Risk Behavior for HIV-Infection The 15 HIV-infected patients with fibromyalgia were significantly more likely to be male (p = O.OOl), had a shorter duration of musculoskeletal April
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TABLE IV
TABLE III Comparisonof Patients With Human lmmunodeficiencyVirus (HIV) Infection and Fibromyalgia to HIV-Infected Patients Without Fibromyalgia
Sex Male Female
9 (60) 3 (20)
Homosexual male of HIVseropositivity
HIV disease Asymptomatic Symptomatic (not AIDS) AIDS Antiretroviral therapy Zidovudine Dedoxyinosine
l! :::,I
9 (60)
0.40 O.Ol§
‘E I:!;
21 (49)
“2 IL’
i: IKP’
33 (77) 5 (11)
0.53 0.78
Journal
of Medicine
268(89) 0.85
Presence of sleep disturbance
12 (80)
257(86) 0.37
Self-reported depressed mood Current Past
5 IKP’
97 (32) 0.00011 122(41) 0.23
7115 (47)
209/301
(69)
0.23
,,...
0.06 0.001~
The low prevalence of arthritis among patients with musculoskeletal symptoms in our study contrasts with other studies of HIV-infected homosexual men that have reported rates of Reiter’s syndrome between 5% and 10% [1,25], perhaps reflecting the high proportion of patients with intravenous drug use as a risk behavior. Berman and co-workers [l] reported arthralgia in 45%, most of whom were homosexual men; unfortunately, fibromyalgia was not assessed. The low rate of true articular disease in our study suggests that the occurence of Reiter’s syndrome or oligoarthritis in patients with HIV infection may be associated with other infectious agents transmitted between homosexual men [26,27]. A significant proportion of our patients complained of myalgias, although most had arthralgias as well. Polymyositis associated with HIV infection and long-term zidovudine therapy may cause myalgia, weakness, and elevated serum creatine kinase levels [S-10,23]. Although we did not routinely measure serum creatine kinase levels, we found no cases of concomitant myopathy and found no difference in the frequency of fibromyalgia in patients treated with zidovudine. Nevertheless, future studies of fibromyalgia in this population should probably include measurements of creatine kinase to fully exclude low-level myopathy. Of the 20 patients with HIV infection and chronic musculoskeletal symptoms in our study, 75% had
The overall rate of arthritis was low in our patient population; two patients had oligoarthritis and none had Reiter’s syndrome or psoriatic arthritis. The American
0.0021
14(93)
..
COMMENTS
1992
65 2 70
0.001*
*Mean * sranaaro aevlauon. tNo. (%I. tp SO.01.
symptoms (p = 0.002), and more commonly reported current, depressed mood (p = 0.0001) than did the 301 patients with fibromyalgia and no known risk factors for HIV infection (Table IV). No significant differences were noted between the two groups in the proportion of patients with symptoms characteristic of fibromyalgia syndrome, such as fatigue, sleep disturbance, and the presence of multiple tender points. The high predominance of males probably reflects the HIV patient population. The decreased duration of musculoskeletal symptoms may have been due to the exclusion of patients in the HIV-infected group with symptoms greater than 24 months prior to HIV serodiagnosis, differences in referral patterns, and the fact that most patients followed in the HIV clinic had been followed for a short period of time, or may reflect the overall high mortality rate associated with HIV infection. The increased rate of current self-reported depressed mood may be related to the patients’ HIV infection or intravenous drug use.
April
26 rt 24
34 (11) 267(89)
due 0.10
Presence of fatigue
Proportion with multiple tender points(zll/lB)
*Mean i standard deviation. tNo. (%I. $Riskfactonotherthan intravenousdruguse WDU) and homosexualnot listed. *p SO.01.
372
7 (47)+ 8 (53)
Mean duration of musculoskeletal symptoms (mo)
249 f 184 206+ 164 0.46
depressed mood
Past
22.1 i: 14.7
Sex Male Female
0.73
l: iFP’
CD4 lymphocyte count/mm3 Se;lfgted
33.7 i: 14.3
ii 1%
37.5 + 7.6* 42.9i: 10.2
Mean age (y)
0.03 :?I I:;;
factort
Me;n$ration m
Fibromyalgia Without Known With HIV HIV Risk Infection Factors (tl = 15) (n = 301)
37.5 i 7.6* 37.0f 6.5 0.81
Mean age(y)
HI:;;
Comparisonof Fibromyalgia Patients With HIV Infection to Fibromyalgia Patients Without Known HIV Risk Factors
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FIBROMYALGIA
definite or probable fibromyalgia syndrome. Based on a denominator of 140 patients, we estimate a prevalence of fibromyalgia syndrome of approximately 11% in this population of patients with HIV infection. The finding of an association between fibromyalgia and HIV infection in our series confirms Buskila’s studies in homosexual men [14], in which approximately 20% of patients met the Smythe criteria for fibromyalgia [14]. The Smythe criteria differ somewhat from the American College of Rheumatology (ACR) criteria [20] utilized in this study in that only tenderness on tender point examination is required rather than specific symptoms. As a result, the Smythe criteria may overestimate the true prevalence of fibromyalgia syndrome. We found that eight patients with HIV infection and chronic musculoskeletal symptoms had between eight and 10 tender points-less than the 11 required by the ACR criteria. While these patients were considered to have probable fibromyalgia, it is possible that this was an incorrect diagnosis. We consider this unlikely, however, since using eight tender points as the minimum number required for the diagnosis in combination with the symptom criterion of widespread pain still has high sensitivity and specificity for diagnosis [20]. It is possible that intravenous drug use may confound the association of fibromyalgia with HIV infection, even though a recent review of the rheumatic manifestations of substance abuse did not include fibromyalgia syndrome [29]. Nevertheless, a prospective assessment of fibromyalgia in HIV-seronegative intravenous drug users should be studied to exclude this possibility. The association with fibromyalgia syndrome and HIV infection may also be related to depression. A lifetime history of major depression has been reported in as many as 50% to 70% of patients with fibromyalgia syndrome [18,30,31]. In most of these patients, a history of major depression preceded symptoms attributable to fibromyalgia syndrome, and most patients were not found to have major depression at the time that fibromyalgia was diagnosed [18,30,31]. A recent study has also found that the central clinical features of fibromyalgia syndrome, such as the number of pain sites, tender points, fatigue, and poor sleep, were independent of psychologic status [32]. Unfortunately, relatively little is known about the prevalence of depression in the setting of HIV infection, particularly in HIVinfected patients with intravenous drug use as a risk factor, but it is likely to be highly prevalent. Our data indicate that current, self-reported depressed mood, while more common in HIV-infected fibromyalgia patients compared to those without known risk factors for HIV infection, was not significantly different in frequency from non-fibromyal-
SYNDROME
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ET AL
gia, HIV-infected patients. These data suggest that current, self-reported depressed mood is the result of HIV infection. Past self-reported depressed mood seemed to be significantly more frequent in those HIV-infected patients with fibromyalgia compared to those without fibromyalgia, but not significantly different in frequency when fibromyalgia patients with HIV infection were compared to those without known risk factors for HIV infection. This seems to indicate that prior depression as a risk factor for fibromyalgia is operating in patients with and without HIV infection. One limitation of our observations with respect to depression is that we used self-reported depressed mood and not a validated depression inventory in all patients. Therefore, our results should be viewed as preliminary until depression can be assessed in this population using a validated depression inventory. Such an inventory will need to control for symptoms of HIV infection (weight loss, fatigue, etc.), and fibromyalgia (somatic pain and fatigue) that confound the assessment of depression using many conventional inventories. Chronic infection is another possible explanation for the association of fibromyalgia syndrome and HIV infection. Both fibromyalgia syndrome and chronic fatigue syndrome have been associated with chronic viral infection [19,33,34]. Preliminary reports have linked human herpes virus type 6 [35,36], parvovirus B19 infection [37], and Coxsackie B2 infection [38] to these syndromes. There has also been an association of parvovirus B19 and hematologic complications of HIV infection [39]. Recent reports have also linked fibromyalgia syndrome to Lyme disease [40,41]. Therefore, chronic HIV infection may be a risk factor for fibromyalgia syndrome. In summary, fibromyalgia syndrome was a common cause of chronic musculoskeletal symptoms in our patients with HIV infection. Identification of fibromyalgia syndrome in these patients coupled with appropriate treatment may improve their quality of life and avoid unnecessary diagnostic and therapeutic interventions. Furthermore, the association of HIV infection and fibromyalgia syndrome may provide an important opportunity to further study the association of depression and chronic viral infection in this common rheumatic disorder.
ACKNOWLEDGMENT We are grateful to Dr. Don L. Goldenberg
for reviewing
the manuscript.
REFERENCES 1. Berman-A, Espinoza LR, Diaz JD, et al. Rheumatic manifestations of human immunodeficiency virus infection. Am J Med 1988; 85: 59-64. 2. Winchester R, Bernstein H, Fischer H. Enlow R, Solomon G. The co-occurence of of Reiter’s syndrome and acquired immunodeficiency. Ann Intern Med 1987; 106: 19-26.
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