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Musculoskeletal syndromes associated with acne
Musculoskeletal
Syndromes
Associated
With Acne
By Robert H. Knitzer and Barbara White Needleman The acne conglobata (AC)-, acne fulminans (AFI-, and isotretinoin-associated musculoskeletal syndromes are three distinct clinical entities. The AC-associated musculoskeletal syndrome occurs primarily in black men over the age of 22, who develop sacroilitis with or without a peripheral arthropathy. In contrast, the AF-associated musculoskeletal syndrome is found almost exclusively in white male teenagers. Fever, weight loss, and arthralgias are prominent components of this syndrome. A unique feature of the AFassociated musculoskeletal syndrome is osteolytic lesions that occur most frequently in the clavicle, sternum, long bones, and ilium. The
I
N 1959, Burns and Coleville reported the first case in the English literature of arthritis occurring in the setting of severe acne.’ Since then, there have been at least 59 additional case reports describing musculoskeletal involvement in acne,2-3o indicating that this is not a rare association. In addition, isotretinoin (13-cisretinoic acid), a widely accepted treatment of severe acne, has been reported to cause musculoskeletal abnormalities.3’-42 The musculoskeletal signs and symptoms associated with acne or its treatment may suggest primary rheumatologic diseases, septic arthritis, or osteomyelitis. Nonetheless, they are not discussed in major internal medicine,43,” rheumatology,45,46or orthopedic textbooks,47 and specialists in these fields may not be cognizant of them. Lack of international agreement on the classification of acne has led to confusion regarding which musculoskeletal findings are associated with the different forms of acne.48 Therefore, in reviewing those cases in which musculoskeletal abnormalities were associated with acne and not isotretinoin therapy, we first categorized the case description as acne conglobata (AC), its subgroup the follicular occlusion triad (FOT), or acne fulminans (AF). Fifteen cases were designated AC,‘-’ based on the presence of classic AC lesions with polyporous comedones, cysts, deep abscesses, draining sinuses, bridging scars,48,49and the absence of an acute illness with ulcerating inflammatory lesions.z-4 In the absence of these criteria, the authors’ classification of the lesions as AC was accepted.5 Five of Seminars in Arthritis andRheumatism,
isotretinoin-associated musculoskeletal syndrome occurs with equal frequency in male and female acne patients. Mild, transient myalgias and arthralgias are very common and do not require discontinuation of isotretinoin therapy. Asymptomatic, small, hyperostotic lesions of the spine occur in approximately 10% of acne patients with the isotretinoin-associated musculoskeletal syndrome. Copyright o 7991 by W.B. Saunders Company INDEX WORDS: isotretinoin.
Acne; arthritis;
bone lesions;
the 15 AC cases were also included within the FOT subgroup,4,5 indicating the concomitant presence of AC with hidradenitis suppurativa and dissecting cellulitis of the scalp.50Forty-one cases were designated AF,‘26-30based on the description of crusting, ulcerative lesions with hemorrhagic, gelatinous centers18~4sor an acute severe illness accompanied by worsening acne with deep dermal involvement. The acne in four patients with musculoskeletal abnormalities could not be further classified as AC or AF.“’ Other cases of acne and musculoskeletal abnormalities were excluded if the patient had a coexisting disease with known rheumatologic manifestations, ie, Crohn’s disease,’ Reiter’s syndrome,4’52sarcoidosis,53 osteomyelitis,52 or human immunodeficiency virus infection.5 After classification of each case, the musculoskeletal
From the Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland, Baltimore, MD, and the Research Service, Veterans Adminirrration Medical Center, Baltimore, MD. Dr Needleman is a recipient of a VA Research Associate Career Development Award. Robert H. Knitzer, MD: Fellow, Division of Rheumatology and Clinical Immunology, University of Maryland, Baltimore, MD: Barbara White Needleman, MD: Associate Professor of Medicine, Division of Rheumatology and Clinical Immunology, Universityof Maryland and the Research Service, Veterans Administration Medical Center, Baltimore, MD. Address reprint requests to Barbara White Needleman, MD, University of Maryland. MSTF Rm 8-34B, 10 S Pine St, Baltimore, MD 21201. Copyright o 1991 by H?B. Saunders Company 0049-0172/91/2004-0004$5.0010
Vol20, No 4 (February), 1991: pp 247-255
247
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KNITZER AND NEEDLEMAN
signs, symptoms, and laboratory results were compared among the groups. The clinical presentations of patients with AC or AF or patients who had received isotretinoin therapy were unique. This review describes the characteristics of these three distinct acne-associated musculoskeletal syndromes (Tables 1 and 2).
Acne is the most common of all skin diseases. In acne vulgaris (AV), an abnormality exists in the sebaceous follicle. It is postulated that androgenic stimulation at the time of puberty leads to an overabundance of sebum production and hyperkeratosis with subsequent follicular plugging. The obstructed glands then serve as a nidus for colonization with bacteria such as Corynebactetium ucnes’5~1sand staphylococcal species.1,‘8~zo The type of acne lesion depends on the depth of inflammation in the dermis. Superficial involvement causes comedones, papules, and pustules, whereas deeper subcutaneous invasion leads to nodules and cysts. The lesions of AV occur primarily on the face, posterior neck, back, and chest. Acne conglobata, FOT, and AF are all more severe forms of acne. It is these forms of acne that are associated with musculoskeletal abnormalities. MUSCULOSKELETAL
SYNDROME
AC is less common than AV, which it may follow. It is more common in whites than blacks, with an incidence of 3% in white adolescent males.48 The lesions of AC arise from a deeper dermal inflammation than is present in AV, and occur on the buttocks, thighs, and upper arms, as well as the typical locations of AV lesions.4s,49 Skin biopsies of these lesions show significant inflammation, engorged vessels, mononuclear cell infiltrates, foreign body granulomas, and Table 1: Classification
of Musculoskeletal
Syndromes Associated With Acne Acne conglobata-associated
Isotretinoin-associated
musculoskeletal
musculoskeletal
syn-
syndrome
of Musculoskeletal
Syndromes Associated With Acne Characteristic
AC
AF
lsotretinoin 215
Age (years)
>22
122
Gender (F:M)
1:4
1:37
1:l
black
white
ND
Race Constitutional
-
+
-
Myalgias
-
+
Myositis
-
+
+ -
symptoms
ACNE: AN OVERVIEW
THE AC-ASSOCIATED
Table 2: Characteristics
Arthralgias
+
+
Arthritis
+
Bone lesions
+ -
+ -
+
-
Skeletal hyperostoses
-
-
+
Abbreviations: AC, acne conglobata; AF, acne fulminans; ND, not described.
fibrosis.48 Healing occurs over many years and leaves bridges of scar tissue. Individuals with FOT form a subgroup of AC patients with concurrent hidradenitis suppurativa and dissecting cellulitis of the scalp. Each results from the same pathological process of follicular hyperkeratosis with occlusion and retention of sebaceous products.” The onset of musculoskeletal symptoms in patients with AC usually coincides with an exacerbation of the acne condition. However, there are exceptions in which the musculoskeletal signs and symptoms may precede an acne flare by 2 to 5 years or follow one by 21 years.’ Patients with musculoskeletal abnormalities and AC without FOT and patients with FOT are similar with respect to age, gender, and race. The age of patients with musculoskeletal abnormalities is 22 to 49 years (median age, 36 years) in AC patients without FOT and 22 to 46 years (median age, 35 years) in FOT patients. Eighty percent of patients in each group are male. In contrast to AC patients in the general population, who are predominantly white:’ 85% of patients with the AC-associated musculoskeleta1 syndrome are black. Patients with AC without FOT and patients with FOT have similar clinical presentations. None exhibit constitutional symptoms of fever or weight loss. All have arthritis (Table 3). The pattern of joint involvement resembles that seen in seronegative spondyloarthropathies. Sacroiliitis occurs in 73% of AC patients,3-s including
ACNE-ASSOCIATED
MUSCULOSKELETAL
Table 3: Musculoskeletal
249
SYNDROMES
Manifestations
of Acne Conglobata,
the Follicular Occlusion Triad,
and Acne Fulminans
Manifestation
All Patients
Total AC
AC Without FOT
FOT
Number (%)
Number (%)
Number (%)
Number (%)
Myalgias
10 (17)
0
0
0
Myositis
3 (5)
0
0
0
2 (20)
Arthralgias
37
(62)
Arthritis
33
(55)
4 (27) 15 (100)
10 (100)
2 (40) 5 (100)
Sacroiliitis
15 (25)
11 (73)
7 (70)
4 (80)
Bone lesions
17 (28)
1 (7)
1 (10)
0
Total patients
60
15 (100)
10 (100)
Abbreviations:
(100)
5 (100)
41
(100)
AC, acne conglobata; FOT, follicular occlusion triad; AF, acne fulminans.
Note. From the reported data, it is not possible to clearly classify the acne in four patients as AC, FOT, or AF. These four patients are, however, included in the total patient data.
of patients with FOT (Tables 3 and 4).4,5 Involvement of the sternoclavicular joints and spine has also been described (Table 4).3-5 The peripheral joints most frequently involved with arthritis in AC patients are the ankles and the joints of the feet (Table 4). The shoulder, elbow, wrist, hand, hip, and knee joints are affected in some individuals.‘” Periph80%
Table 4: Distribution
eral joint involvement is symmetrical 60% of the time. No synovial fluid analyses have been reported in this group of patients. Radiological evaluation of joints in AC patients affected with arthritis has shown a variety of abnormalities, including soft tissue swelling, periarticular osteoporosis, cartilage loss with joint space narrowing, erosions, periostitis, new
of Arthritis in Acne Fulminans and Acne Conglobata Total Patients Number (%)
AC Patients Number (%)
4 (14)
3 (20)
1 (7)
Cervical
6 (21)
6 (40)
0
Thoracic
4 (14)
3 (20)
1 (7)
11 (38)
9 (60)
2 (14)
14 (48)
11 (73)
3 (21)
Joint Involved
AF Patients Number (%)
Axial Sternoclavicular Spine
Lumbo-sacral Sacroiliac Appendicular Acromioclavicular
3 (TO)
2 (13)
1 (7)
Shoulder
1 (3)
1 (7)
0 0
Elbow
1 (3)
1 (7)
Wrist
6 (21)
4 (27)
1 (7)
Hip
7 (24)
4 (27)
3 (21)
Knee
11 (38)
3 (20)
8 (57)
Ankle
9 (31)
6 (40)
3 (21)
Subtalar
1 (3)
0
1 (7)
TarsaVlP
9 (31)
9 (60)
0
Abbreviations:
AC, acne conglobata; AF, acne fulminans.
Note. 33 of 60 total patients with musculoskeletal abnormalities associated with acne had arthritis (55%), but information on specific joint involvement was available for only 29 of these patients; therefore data are given as a percentage of these 29 patients. Fifteen of these 29 patients were classified as having AC, including 5 patients with the follicular occlusion triad, and 14 patients were classified as having AF.
250
KNITZER AND NEEDLEMAN
bone formation, and alignment abnormalities. Coarse paravertebral ossifications, hyperostoses, smooth anterior syndesmophyte formations with corner erosions and sclerosis, and calcified tendons also have been reported and are identical to those seen in seronegative spondyloarthropathies.3-5 Arthralgias are present in approximately one fourth of the AC patients and typically involve the elbows, hips, knees, ankles, and small joints of the feet.2’3’5A single AC patient had lytic bone lesions in the right ulna and fourth thoracic vertebrae.2 Muscle involvement is not a part of the musculoskeletal syndrome in AC or FOT. The course of the musculoskeletal disease in most AC patients is one of recurrent episodes of axial and peripheral joint arthritis or arthralgias, which may continue to occur for weeks to years after their initial presentation.3-5 It is unknown whether radiological abnormalities reverse to normal over time. THE AF-ASSOCIATED
MUSCULOSKELETAL
SYNDROME AF is the most aggressive and destructive form of acne. Affected individuals have a prior history of AV; the disease worsens acutely and is sometimes precipitated by viral illness,17,22 stress and fatigue,8X’8or institution of isotretinoin therapy.” The hallmark lesion of AF is an exquisitely tender, erythematous ulcer containing reddish-yellow gelatinous material covered by a friable hemorrhagic crust.‘sX48Cultures of skin lesions have grown Corynebacterium acnes, l5 staphylococcal species,‘z7x22Pityrosporon
ovale,” Propionibacterium acnes, ‘SOEscherichia coli, l4and proteus species.” On histologic exam-
ination, AF lesions show an intense polymorphonuclear infiltrate with invasion of the follicle wall, pronounced edema, and vascular hyperplasia with perivascular histiocytic and lymphocytic infiltrates.” Healing of the inflamed areas leaves extensive scarring. The onset of musculoskeletal symptoms in AF patients temporally coincides with the onset of AF. These patients are usually male, ages 13 to 22 years (median age, 16 years); only two of the reported cases have been female.7’3oNinetyeight percent of reported AF patients with musculoskeletal symptoms are white. Of
note, fever and weight loss are present in 100% of AF patients with musculoskeletal sympFever as high as 41°C has toms. ‘~‘~11~1*~15,16~‘8~2o,27 been reported.21 Weight loss may be dramatic, with documented losses of 12 kg occurring as quickly as 1.5 kg/wk.‘,‘* Patients with AF have a different spectrum of musculoskeletal abnormalities than patients with AC (Table 3). The most distinctive feature of the AF-associated musculoskeletal syndrome is the presence of painful bone lesions, found in 39% of patients. In approximately 50% of patients with bone lesions, multiple osseous defects are present,6~8~‘0~12S14’U.“.27~29 with as many as nine lesions reported in one patient.27 The bone lesions generally become painful at the time of the acne flare, although they may become symptomatic several weeks prior to the worsening of the skin condition.*l Asymptomatic bone lesions may also be present and account for about one quarter of all bone lesions. These asymptomatic lesions are detected when a radionuclide (99mTc)bone scan is performed to evaluate symptomatic lesions elsewhere. Bone scanning shows increased uptake of tracer in areas of both symptomatic and asymptomatic bone lesions. Radiographic evaluation of symptomatic bone lesions are abnormal in over 90% of cases and show lytic bone lesions12,21,23 or periosteal reaction.7’8 Most lesions are located in the clavicle, sternum, and long bones of the extremities (Table 5). These locations would be atypical for osteomyelitis, which, in this age group, characteristically occurs in the epiphyses of long bones and only
Table 5: Distribution
of Bone Lesions in the
Acne Fulminans Musculoskeletal Location
Syndrome
Number of Lesions 6 6
Clavicle Sternum Tibia
5
Humerus
4
Greater
trochanter
3
Ilium
3
Femur
2
Fibula
2
Note. One lesion has been reported in each of the following areas: cervical spine, thoracic spine, acromion,
ulna, carpal,
metacarpal, ankle, subtalar, tarsal, and metatarsal joints.
ACNE-ASSOCIATED
MUSCULOSKELETAL
251
SYNDROMES
rarely involves the clavicle.” Biopsies of the bone lesions have only yielded foci of chronic inflammation,19,21,23 marrow fibrosis,24 or normal tissue,‘* without evidence for infection. Patients with these bone lesions may have elevated serum alkaline phosphatase levels.14,‘9 Arthritis is present in one third of patients with the AF-associated musculoskeletal syndrome. The arthritis is usually nondeforming, self-limited, and has a predilection for the knees; 57% of AF patients with arthritis have involvement of this joint (Table 4). Arthritis of small joints occurs less frequently in AF patients than in AC patients. Sacroiliitis is also uncommon, occurring in only 7% of all AF patients with musculoskeletal abnormalities (Table 3) and in 21% of those AF patients who have arthritis (Table 4). Diffuse areas of demineralization’x’8 periosteal new bone formation, and transverse bands of radiolucency may be seen on radiographs of the joints.18 Biopsy of synovium from affected joints has shown only mild hyperplasia with moderate numbers of lymphocytes and plasmacytes.” Whereas frank arthritis is less common in the AF-associated musculoskeletal syndrome than in the AC-associated musculoskeletal syndrome, arthralgias and muscle involvement are more common (Table 3). Arthralgias are present in 80% of patients with the AF-associated musculoskeletal syndrome, with the hips and shoulders the most commonly involved sites. Myalgias also frequently involve the hip and shoulder girdles. Overt myositis has been reported in 3 of 41 (7%) AF cases with musculoskeletal symptoms, and, when present, has been uniformly accompanied by muscle weakness.8”h.‘9Although creatinine phosphokinase levels have been within normal limits,“,16in all 3 patients, electromyography has shown fibrillations and positive wave patterns consistent with myositis.R,16.‘9 In two patients with myositis, results of muscle biopsy showed scattered foci of muscle fiber necrosis associated with mononuclear cell infiltrates.16.19In one patient in whom myalgias and weakness were present and electromyography results were abnormal, the muscle biopsy was nondiagnostic. Because patients with the AF-associated musculoskeletal syndrome present with an acute
process including fever, weight loss, leukocytosis, and bone lesions, the possibility of sepsis or osteomyelitis is routinely raised. Exhaustive investigations for a nidus of infection other than the skin have been unrevealing. Blood cultures have been negative except for sporadic growth of propionibacterium and staphylococcal species thought to be contaminants.‘~11’14~18~21~22~24 Culture and microscopic examination of cerebrospinal and synovial fluids have been sterile.“.21 Bone biopsy specimens have been culture negative except in one case where P acnes was isolated.*’ The prognosis of patients with the AFassociated musculoskeletal syndrome is variable. With resolution of the initial acne flare, there may be immediate control of all musculoskeletal symptoms and no further problems despite subsequent acne exacerbations.” Bone lesions may resolve within 1 month of effective therapy and control of the acne.14 However, more commonly, there are episodes of arthritis, arthralgias, and myalgias, which may recur over many subsequent years.8~‘o~13~‘7~‘8 These recurrent episodes of musculoskeletal symptoms may accompany a flare of acne or may occur when the skin disease is under good contro1.18 In some patients, exacerbations of their musculoskeletal symptoms may be precipitated by the tapering of steroid therapy used to treat the underlying acne.8,29 THE ISOTRETINOIN MUSCULOSKELETAL SYNDROME IN ACNE PATIENTS
Isotretinoin is a synthetic derivative of vitamin A, used since 1976 with benefit in the treatment of cystic and congobate acne”4 and disorders of keratinization.54 In patients treated with isotretinoin for diseases other than acne, premature epiphyseal closure,3’ transient mild musculoskeletal symptoms,42 and symptomatic skeletal hyperostoses resembling diffuse idiopathic skeletal hyperostosis have been reported.33,55These abnormalities occur more frequently in patients treated with isotretinoin doses greater than 2 mg/kg/d or with continuous therapy over several years.” These side effects of isotretinoin are not unexpected, because vitamin A itself can cause bone and joint pain, calcifications in pericapsular ligaments3* and, in children, cortical thickening of tubular bones,
252
metaphyseal cupping and splaying, and premature fusion of the growth plate?“” Musculoskeletal abnormalities among patients taking isotretinoin for acne occur with equal frequency in males and females, whose ages range from 15 to 52 years. Diffuse myalgias and arthralgias are the most common musculoskeletal symptoms, occurring in 27% in one prospective study of 120 patients41 and “nearly all patients” in another prospective study of 96 patients.32 However, these myalgias and arthralgias are mild and resolve spontaneously within a few days, without discontinuation of the isotretinoin therapy.37 Skeletal hyperostosis is the next most common musculoskeletal abnormality associated with isotretinoin therapy for acne, occurring in 24 of 220 reported acne patients who were treated with isotretinoin and who subsequently developed musculoskeletal symptoms.32’41The hyperostoses tends to occur in the axial skeleton, especially the cervical spine.39 In the prospective study of Kilcogne et a1,32 10 of 96 patients developed small horizontal spurs extending from the anterior margin of one or more vertebral bodies. These spurs differ from those seen in diffuse idiopathic skeletal hyperostosis in their small size and lack of involvement at multiple levels of the spine. Spurs may develop as early as 6 months after initiation of isotretinoin therapy.32 The occurrence of these skeletal hyperostoses is not dose-related when isotretinoin is taken in doses less than 2 mg/kg/ d.32,41There is no correlation between radiographic changes and musculoskeletal signs or symptoms in these patients.32.4’It is not known if these hyperostoses undergo regression after cessation of treatment.39 Other isotretinoin-associated musculoskeletal abnormalities include soft tissue calcification of tendons and ligaments33’40and arthritis. One acne patient treated with isotretinoin developed a noncalcified Achilles tendonitis.37 Three patients developed arthritis.37,38In one patient with isotretinoin-induced arthritis, in whom a diagnostic arthrocentesis was performed, the synovial fluid white blood cell count was 2,3OO/uL with 90% polymorphonuclear leukocytes, and cultures were negative3’ in two of the three patients. The arthritis resolved quickly without sequelae and without stopping ther-
KNITZER AND NEEDLEMAN
apy.37,38In the third patient, the arthritis resolved shortly after isotretinoin was stopped and indomethacin was begun.37 Some patients, particularly those with AC, may be started on isotretinoin therapy when their acne flares. If these patients subsequently develop musculoskeletal complaints, the physician must determine whether these symptoms are related to the underlying acne or to the isotretinoin therapy. If the patient has severe or persistent arthralgias or myalgias, frank arthritis, or myositis, it is more likely that these complaints are related to the acne, rather than the isotretinoin therapy. LABORATORY
EVALUATION
Laboratory findings are similar in patients with either the AC-associated or the AFassociated musculoskeletal syndromes. Elevated erythrocyte sedimentation rates, leukocytosis including left shift and toxic granulations, and anemia are present in many patients. Thrombocytosis has been reported in one patient with AF.30 The severity, extent, and rapidity of the acne exacerbation seem to correlate with the degree of the laboratory abnormality. Hypergammaglobulinemia with a selective increase in immunoglobulin (1g)A or IgG,3,14Z16 or polyclonal increases in IgG, IgA, and IgM may occur.22 Renal function remains unchanged from baseline values, although urinalyses in some AF patients may show microscopic hematuria of unknown etiology.12,16,22’24 Antinuclear antibodies and IgM rheumatoid factors are not present in patients’ sera. Component C3 levels are decreased,” norma1,14~16~20~21~59 or increased,5g while C4 levels are norma1’4Z’6’20’21 or increased.“,59 Levels of circulating immune complexes are normal’ or elevated.3x25 When tested, delayed-type hypersensitivity skin test responses have been abnormal in most AC and AF patients with musculoskeletal symptoms, with no response to challenge with tuberculin, trichophyton, or dinitrochlorobenzene.aT62 In contrast, patients with AV or AC without musculoskeletal abnormalities respond to these same antigens.61 The significance of this finding is unknown. T cell proliferative responses have been normal when stimulated with the mitogen phytohemagglutinin or with purified protein There is a single report derivative antigen.6.61’63
ACNE-ASSOCIATED
MUSCULOSKELETAL
253
SYNDROMES
of uncharacterized “decreased T suppressor cell function.“24 Laboratory studies of patients with the isotretinoin-associated musculoskeletal syndrome do not show anemia, leukocytosis, or elevated erythrocyte sedimentation rates. However, serum triglycerides have occasionally been elevated.64 PATHOGENESIS
The original description of acne-associated arthritis by Burns and Coleville was one which suggested the presence of septicemia.’ This description may have fostered the hypothesis that infection was responsible for the musculoskeletal manifestations associated with acne. Although there have been isolated case reports of C acnes osteitis and osteomyelitis,52 the results of cultures in the vast majority of cases have not substantiated infection as a pathophysiological mechanism in the acne-associated musculoskeletal syndromes. Other investigators have speculated that the myalgias, bone lesions, and joint complaints may represent a “reactive arthritis.” It has been postulated that these musculoskeletal abnormalities represent a hypersensitivity response in susceptible individuals to sebum, bacterial antigens, or altered skin antigens.1r8.65In support of this process, Williamson et al have found that some AF patients develop an exaggerated area of induration with central necrosis and a surrounding erythematous flare in response to intradermal P awes antigen.26 Purvel has reported that patients with AC have increased lymphocyte proliferation in response to P acnes, but not to phytohemagglutinin.” In addition, some AC patients develop antibody against P acnes. 6
It has also been proposed that acne-associated musculoskeletal signs and symptoms reflect immune complex-mediated pathological events.25 This hypothesis is supported by the clinical findings of splinter hemorrhages,16 erythema nodosum,25zz6hematuria,12~16~1s~22~24 myositis, 8,16,‘9 diffise increases in serum y globulins,22 and steroid responsiveness.65 However, circulating immune complexes have been found only in those AP patients with musculoskeletal abnormalities who also have erythema nodosum.*’ Host factors in acne patients may contribute
to susceptibility toward musculoskeletal complications. There are two reports of monozygotic twins who developed virtually identical presentations of the AF-associated musculoskeletal syndrome within 2 months of each other.“,” HLA-B27 does not appear to be associated with the with development of the clinical picture of a seronegative spondyloarthropathy in AC patients. When tested, HLA-B27 antigen was absent in 13 of 14 AC patients. THERAPY
Therapy for the musculoskeletal syndromes associated with AC and AF consists of aggressive treatment of the underlying acne, combined with therapy for the musculoskeletal abnormalities themselves. Milder forms of acne may respond to topical or oral antibiotics. More severe disease often requires the addition of synthetic retinoids, particularly isotretinoin. If the above drugs are not effective in controlling the acne, local and systemic steroid preparations may be used. Other drugs which have been reported to be effective in severe acne include Dapsone (Jacobus Pharmaceutical Co, Inc, Princeton, NJ)16**land Clofazimine (CibaGeigy, Frolunda, Sweden).’ Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) may be useful in the control of low-grade fever, arthralgias, arthritis, and pain from bone lesions in patients with AC or AF.2,6,29 Monoarthritis or oligoarthritis may respond to intraarticular steroids.7 Most patients with the AF-associated musculoskeletal syndrome have been treated with systemic steroids because their high fevers, progressive weight loss, and joint inflammation were unresponsive to aspirin or NSAIDs. Prednisone, given in doses from 15 to 40 mg/d, has alleviated many of these symptoms within 12 to 72 hours.9,‘4 The myalgias and arthralgias associated with isotretinoin therapy are generally mild and transient and disappear spontaneously without stopping therapy. Similarly, frank arthritis may resolve with joint aspiration or NSAID therapy and not require discontinuation of isotretinoin. ACKNOWLEDGMENTS The authors thank Drs Barry Handwerger Anderson for their review of this manuscript.
and Regina
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KNITZER AND NEEDLEMAN
REFERENCES 1. Bums RE, Coleville JM: Acne conglobata with septicemia. Detroit Dermatological Society, AMA. Arch Dermatol 79:361-363, 1959 2. Ehrenfeld M, Samra Y, Kaplinsky N: Acne conglobata and arthritis; report of a case and review of the literature. Clin Rheumatol5:407-409,1986 3. Bookbinder SA, Fenske NA, Clement GB, et al: Clavicular hyperostosis and acne arthritis. Ann Intern Med 97:615-616,1982 4. Rosner IA, Richter DE, Huettner TL, et al: Spondyloarthropathy associated with hidradenitis suppurativa and acne conglobata. Ann Intern Med 97:520-525, 1982 5. Ellis BL, Shiuer CK, Leisen JJ, et al: Acne-associated spondyloarthropathy: Radiographic features. Radiology 162: 541-545,1987 6. McKendry RJR, Hamdy H: Acne, arthritis, and sacroiliitis. Can Med Assoc J 128:156-158, 1983 7. Statham BN, Holt PJA, Pritchard MH: Acne fuhninansreport of a case with polyarthritis. Clin Exp Dennatol 8:401-404, 1983 8. Cros D, Gamby T, Serratrice G: Acne rheumatism. Report of a case. J Rheumatol8:336-339,198l 9. Davis DE, Viozzi FJ, Miller OF, et al: The musculoskeleta1 manifestations of acne fulminans. J Rheumatol 8:317320,198l 10. Golding DN: Acne and joint disease. J R Sot Med 78:19-20,1985 (suppl 10) 11. Gonzalez T, Gantes M, Bustabad S, et al: Acne fulminans associated with arthritis in monozygotic twins. J Rheumatol 12:389-390,1985 12. Lane JM, Leyden JJ, Spiegel RJ: Acne arthralgia. J Bone Joint Surg 58A:673-675,1976 13. Windom RE, Sanford JP, Ziff M: Acne conglobata and arthritis. Arthritis Rheum 4:632-635, 1961 14. O’Malley BP, Anderson I, Rosenthal FD: Bone lesions in systemic acne (acne fulminans). Br J Dermatol 100:703-705,1978 15. Goldschmidt H, Leyden JJ, Stein KH: Acne fulminans. Arch Dermatol113:444-449,1977 16. Noseworthy JH, Heffernan LP, Ross JB, et al: Acne fulminans with inflammatory myopathy. Ann Neurol 8:6769,198O 17. Thyresson N: Acne conglobata and septicemia. Tram Swed Dermatol Sot 498-499,196l 18. Kelly PA, Burns RE: Acute febrile ulcerative conglobate acne. Arch Dermatol104:182-187,197l 19. Hunter LY, Hensinger RN: Destructive arthritis associated with acne fulminans: A case report. Ann Rheum Dis 39:403-405,198O 20. Darley CR, Currey HLF, Baker H: Acne fulminans with arthritis in identical twins treated with isotretinoin. J R Sot Med 77:328-330,1984 21. Siegel D, Strosberg JM, Wiese F, et al: Acne fulminans with a lytic bone lesion responsive to dapsone. J Rheumatol9:344-346,1982 22. Strom S, Thyresson N, Bostrom H: Acute febrile ulcerative conglobate acne with leukemoid reaction. Acta Derm Venereol53:306-312,1973 23. Pauli S-L, Kokko M-L, Suhonen R, et al: Acne
fulminans with bone lesions. Acta Derm Venereol 68:351355,1988 24. Jemec BE, Rasmussen I: Bone lesions of acne fulminans: Case report and review of the literature. J Am Acad Dermatol20:353-357,1989 25. Kellett JK, Beck MH, Chalmers RJG: Erythema nodosum and circulating immune complexes in acne fulminans after treatment with isotretinoin. Br Med J 290:820, 1985 26. Williamson DM, Cunliffe WJ, Gatecliff M, et al: Acute ulcerative acne conglobata (acne fulminans) with erythema nodosum. Clin Exp Dermatol2:351-354,1977 27. Nault P, Lassonde M, St-Antoine P: Acne fulminans with osteolytic lesions. Arch Dermatol 121:662-664,198s 28. Moschella SL: Report of a case of acne conglobata and arthritis. Bull Assoc Mil 13:15-17,1964 29. Engber PB, Marino CT: Acne fulminans with prolonged polyarthralgia. Int J Dermatol19:567-569,198O 30. Wolf R, David M, Feuerman EJ: Acne with acute systemic reaction (acne fulminans?). Cutis 28:210-216,198l 31. Milstone LM, McGuire J, Ablow RC: Premature epiphyseal closure in a child receiving oral 13-cis-retinoic acid. J Am Acad Dermatol7:663-666,1982 32. Kilcoyne RF, Cope R, Cunningham W, et al: Minimal spinal hyperostosis with low-dose isotretinoin therapy. Invest Radio1 21:41-44,1986 33. Pittsley RA, Yoder FW: Retinoid hyperostosis: Skeletal toxicity associated with long-term administration of 13-cis-retinoic acid for refractory ichthyosis. N Engl J Med 308:1012-1014,1983 34. Peck GL, Olsen TG, Yoder FW, et al: Prolonged remissions of cystic and conglobate acne with 13&-retinoic acid. N Engl J Med 300:329-333,1979 35. Ward A, Brogden RN, Heel BC, et al: Isotretinoin: A review of its pharmacological properties and therapeutic efficacy in acne and other skin disorders. Drugs 28:6-37, 1984 36. Ellis CN, Madison KC, Pennes DR, et al: Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol10:1024-1029,1984 37. Matsuoka LY, Wortsman J, Pepper JJ: Acne arthritis during isotretinoin treatment for acne. Arch Intern Med 144:1870-1871,1984 38. Camisa C: Acute arthritis during isotretinoin therapy for acne: J Am Acad Dermatol 15:1061-1062, 1986 39. Pennes DR, Ellis CN, Madison KC, et al: Early skeletal hyperostoses secondary to 13-cis-retinoic acid. Am J Roentgen01 142:979-983,1984 40. McGuire J, Lawson JP: Skeletal changes associated with chronic isotretinoin and etretinate administration. Dermatologica 175:169-181,1987 41. Carey BM, Parkin GJS, Cunliffe WJ, et al: Skeletal toxicity with isotretinoin therapy: A clinico-radiological evaluation. Br J Dermatol119:609-614,1988 42. Hoffman-LaRoche, Inc, Nutley, NJ, Accutane package insert, 1985 43. Wyngaarden JB, Smith LH (eds): Cecil Textbook of Medicine (ed 18). Philadelphia, PA, Saunders, 1985 44. Braunwald E, Isselbacher KJ, Petersdorf RG, et al:
ACNE-ASSOCIATED
MUSCULOSKELETAL
SYNDROMES
(eds): Harrison’s Principles of Internal Medicine (ed 11). New York, NY, McGraw-Hill, 1987 45. Kelly WN, Harris ED, Ruddy S, (eds): Textbook of Rheumatology (ed 3). Philadelphia, PA, Saunders, 1989 46. McCarty DJ (ed): Arthritis and Allied Conditions (ed 10). Philadelphia, PA, Lea & Febiger, 1985 47. Crenshaw AH (ed): Campbell’s Operative Orthopaedics (ed 7). St Louis, MO, Mosby, 1987 48. Plewig G, Khgman AM: Acne: Morphogenesis and Treatment. Berlin, New York, Springer-Verlag, 1975 49. Fitzpatrick TB, Eisen AZ, Wolff K, (eds): Dermatology in General Medicine (ed 3). New York, NY, McGraw Hill, 1987 50. Moschella SL, Hurley HJ (eds): Dermatology (ed 2). Philadelphia, PA, Saunders, 1985 51. Clement GB, Vasey FB, Fenske NA, et al: Acne arthritis: Clinical manifestations, human leukocyte antigens, and circulating immune complexes. Arthritis Rheum 25:S12, 1982 (abstr) 52. Serushan M, Spencer DL, Yeh WLS, et al: Osteomyelitis of cervical spine from Propionibacterium acnes. Arthritis Rheum 25:346-348,1982 53. Houben HHML, Lemmens JAM, Boerbooms AMT: Sacroiliitis and acne conglobata. Clin Rheumatol 4:86-89, 1985 54. Peck CL, Yoder FW: Treatment of lamellar ichthyosis and other keratinizing disorders with an oral synthetic retinoid. Lancet 2:1172-1174, 1976 55. Gerber LH, Helfgott RK, Gross EG, et al: Vertebral abnormalities associated with synthetic retinoid use. J Am Acad Dermatol 10:817-823, 1984
255
56. Caffey J: Chronic poisoning due to excess vitamin A. AJR: 65:12-26,195l 57. Ruby LK, Mital MA: Skeletal deformities following chronic hypetvitaminosis A. J Bone Joint Surg 56A:12831287,1974 58. Frame B, Jackson CE, Reynolds WA, et al: Hypercalcemia and skeletal defects in chronic hypervitaminosis A. Ann Intern Med 80:44-48, 1974 59. Vasey FB, Fenske NA, Clement GB, et al: Immunological studies of the arthritis of acne conglobata and hidradenitis suppurativa. Clin Exp Rheumatol 2:309-311, 1984 60. Michaelson H, Allen PK: Acne conglobata. Arch Dermatol23:49-67,193l 61. Palatsi R: Delayed hypersensitivity and febrile acne conglobata. Acta Derm Venereol57:51-53, 1977 62. Rajka G: On cell-mediated immunity in acne conglobata. Acta Derm Venereol57:141-143,1977 63. Rajka G, Froland S: Lecture on the XI. Stand Congr Allergology, Helsinki, May 25, 1973 64. Katz RA, Jorgensen H, Nigra TP: Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol116:1369-1372, 1980 65. Farber EM, Claiborne ER: Acne conglobata: Use of cortisone and corticotropin in therapy. Calif Med 81:76-78, 1954 66. Puhvel SM, Adirian D, Weintraub J, et al: Lymphocyte transformation in subjects with nodulocystic acne. Br J Dermatol97:205-211, 1977 67. Good AE, Kawanish H, Schultz JS: HLA B27 in blacks with ankylosing ‘spondylitis or Reiter’s disease. N Engl J Med 294:166-167, 1976
Syndromes
Associated
With Acne
By Robert H. Knitzer and Barbara White Needleman The acne conglobata (AC)-, acne fulminans (AFI-, and isotretinoin-associated musculoskeletal syndromes are three distinct clinical entities. The AC-associated musculoskeletal syndrome occurs primarily in black men over the age of 22, who develop sacroilitis with or without a peripheral arthropathy. In contrast, the AF-associated musculoskeletal syndrome is found almost exclusively in white male teenagers. Fever, weight loss, and arthralgias are prominent components of this syndrome. A unique feature of the AFassociated musculoskeletal syndrome is osteolytic lesions that occur most frequently in the clavicle, sternum, long bones, and ilium. The
I
N 1959, Burns and Coleville reported the first case in the English literature of arthritis occurring in the setting of severe acne.’ Since then, there have been at least 59 additional case reports describing musculoskeletal involvement in acne,2-3o indicating that this is not a rare association. In addition, isotretinoin (13-cisretinoic acid), a widely accepted treatment of severe acne, has been reported to cause musculoskeletal abnormalities.3’-42 The musculoskeletal signs and symptoms associated with acne or its treatment may suggest primary rheumatologic diseases, septic arthritis, or osteomyelitis. Nonetheless, they are not discussed in major internal medicine,43,” rheumatology,45,46or orthopedic textbooks,47 and specialists in these fields may not be cognizant of them. Lack of international agreement on the classification of acne has led to confusion regarding which musculoskeletal findings are associated with the different forms of acne.48 Therefore, in reviewing those cases in which musculoskeletal abnormalities were associated with acne and not isotretinoin therapy, we first categorized the case description as acne conglobata (AC), its subgroup the follicular occlusion triad (FOT), or acne fulminans (AF). Fifteen cases were designated AC,‘-’ based on the presence of classic AC lesions with polyporous comedones, cysts, deep abscesses, draining sinuses, bridging scars,48,49and the absence of an acute illness with ulcerating inflammatory lesions.z-4 In the absence of these criteria, the authors’ classification of the lesions as AC was accepted.5 Five of Seminars in Arthritis andRheumatism,
isotretinoin-associated musculoskeletal syndrome occurs with equal frequency in male and female acne patients. Mild, transient myalgias and arthralgias are very common and do not require discontinuation of isotretinoin therapy. Asymptomatic, small, hyperostotic lesions of the spine occur in approximately 10% of acne patients with the isotretinoin-associated musculoskeletal syndrome. Copyright o 7991 by W.B. Saunders Company INDEX WORDS: isotretinoin.
Acne; arthritis;
bone lesions;
the 15 AC cases were also included within the FOT subgroup,4,5 indicating the concomitant presence of AC with hidradenitis suppurativa and dissecting cellulitis of the scalp.50Forty-one cases were designated AF,‘26-30based on the description of crusting, ulcerative lesions with hemorrhagic, gelatinous centers18~4sor an acute severe illness accompanied by worsening acne with deep dermal involvement. The acne in four patients with musculoskeletal abnormalities could not be further classified as AC or AF.“’ Other cases of acne and musculoskeletal abnormalities were excluded if the patient had a coexisting disease with known rheumatologic manifestations, ie, Crohn’s disease,’ Reiter’s syndrome,4’52sarcoidosis,53 osteomyelitis,52 or human immunodeficiency virus infection.5 After classification of each case, the musculoskeletal
From the Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland, Baltimore, MD, and the Research Service, Veterans Adminirrration Medical Center, Baltimore, MD. Dr Needleman is a recipient of a VA Research Associate Career Development Award. Robert H. Knitzer, MD: Fellow, Division of Rheumatology and Clinical Immunology, University of Maryland, Baltimore, MD: Barbara White Needleman, MD: Associate Professor of Medicine, Division of Rheumatology and Clinical Immunology, Universityof Maryland and the Research Service, Veterans Administration Medical Center, Baltimore, MD. Address reprint requests to Barbara White Needleman, MD, University of Maryland. MSTF Rm 8-34B, 10 S Pine St, Baltimore, MD 21201. Copyright o 1991 by H?B. Saunders Company 0049-0172/91/2004-0004$5.0010
Vol20, No 4 (February), 1991: pp 247-255
247
248
KNITZER AND NEEDLEMAN
signs, symptoms, and laboratory results were compared among the groups. The clinical presentations of patients with AC or AF or patients who had received isotretinoin therapy were unique. This review describes the characteristics of these three distinct acne-associated musculoskeletal syndromes (Tables 1 and 2).
Acne is the most common of all skin diseases. In acne vulgaris (AV), an abnormality exists in the sebaceous follicle. It is postulated that androgenic stimulation at the time of puberty leads to an overabundance of sebum production and hyperkeratosis with subsequent follicular plugging. The obstructed glands then serve as a nidus for colonization with bacteria such as Corynebactetium ucnes’5~1sand staphylococcal species.1,‘8~zo The type of acne lesion depends on the depth of inflammation in the dermis. Superficial involvement causes comedones, papules, and pustules, whereas deeper subcutaneous invasion leads to nodules and cysts. The lesions of AV occur primarily on the face, posterior neck, back, and chest. Acne conglobata, FOT, and AF are all more severe forms of acne. It is these forms of acne that are associated with musculoskeletal abnormalities. MUSCULOSKELETAL
SYNDROME
AC is less common than AV, which it may follow. It is more common in whites than blacks, with an incidence of 3% in white adolescent males.48 The lesions of AC arise from a deeper dermal inflammation than is present in AV, and occur on the buttocks, thighs, and upper arms, as well as the typical locations of AV lesions.4s,49 Skin biopsies of these lesions show significant inflammation, engorged vessels, mononuclear cell infiltrates, foreign body granulomas, and Table 1: Classification
of Musculoskeletal
Syndromes Associated With Acne Acne conglobata-associated
Isotretinoin-associated
musculoskeletal
musculoskeletal
syn-
syndrome
of Musculoskeletal
Syndromes Associated With Acne Characteristic
AC
AF
lsotretinoin 215
Age (years)
>22
122
Gender (F:M)
1:4
1:37
1:l
black
white
ND
Race Constitutional
-
+
-
Myalgias
-
+
Myositis
-
+
+ -
symptoms
ACNE: AN OVERVIEW
THE AC-ASSOCIATED
Table 2: Characteristics
Arthralgias
+
+
Arthritis
+
Bone lesions
+ -
+ -
+
-
Skeletal hyperostoses
-
-
+
Abbreviations: AC, acne conglobata; AF, acne fulminans; ND, not described.
fibrosis.48 Healing occurs over many years and leaves bridges of scar tissue. Individuals with FOT form a subgroup of AC patients with concurrent hidradenitis suppurativa and dissecting cellulitis of the scalp. Each results from the same pathological process of follicular hyperkeratosis with occlusion and retention of sebaceous products.” The onset of musculoskeletal symptoms in patients with AC usually coincides with an exacerbation of the acne condition. However, there are exceptions in which the musculoskeletal signs and symptoms may precede an acne flare by 2 to 5 years or follow one by 21 years.’ Patients with musculoskeletal abnormalities and AC without FOT and patients with FOT are similar with respect to age, gender, and race. The age of patients with musculoskeletal abnormalities is 22 to 49 years (median age, 36 years) in AC patients without FOT and 22 to 46 years (median age, 35 years) in FOT patients. Eighty percent of patients in each group are male. In contrast to AC patients in the general population, who are predominantly white:’ 85% of patients with the AC-associated musculoskeleta1 syndrome are black. Patients with AC without FOT and patients with FOT have similar clinical presentations. None exhibit constitutional symptoms of fever or weight loss. All have arthritis (Table 3). The pattern of joint involvement resembles that seen in seronegative spondyloarthropathies. Sacroiliitis occurs in 73% of AC patients,3-s including
ACNE-ASSOCIATED
MUSCULOSKELETAL
Table 3: Musculoskeletal
249
SYNDROMES
Manifestations
of Acne Conglobata,
the Follicular Occlusion Triad,
and Acne Fulminans
Manifestation
All Patients
Total AC
AC Without FOT
FOT
Number (%)
Number (%)
Number (%)
Number (%)
Myalgias
10 (17)
0
0
0
Myositis
3 (5)
0
0
0
2 (20)
Arthralgias
37
(62)
Arthritis
33
(55)
4 (27) 15 (100)
10 (100)
2 (40) 5 (100)
Sacroiliitis
15 (25)
11 (73)
7 (70)
4 (80)
Bone lesions
17 (28)
1 (7)
1 (10)
0
Total patients
60
15 (100)
10 (100)
Abbreviations:
(100)
5 (100)
41
(100)
AC, acne conglobata; FOT, follicular occlusion triad; AF, acne fulminans.
Note. From the reported data, it is not possible to clearly classify the acne in four patients as AC, FOT, or AF. These four patients are, however, included in the total patient data.
of patients with FOT (Tables 3 and 4).4,5 Involvement of the sternoclavicular joints and spine has also been described (Table 4).3-5 The peripheral joints most frequently involved with arthritis in AC patients are the ankles and the joints of the feet (Table 4). The shoulder, elbow, wrist, hand, hip, and knee joints are affected in some individuals.‘” Periph80%
Table 4: Distribution
eral joint involvement is symmetrical 60% of the time. No synovial fluid analyses have been reported in this group of patients. Radiological evaluation of joints in AC patients affected with arthritis has shown a variety of abnormalities, including soft tissue swelling, periarticular osteoporosis, cartilage loss with joint space narrowing, erosions, periostitis, new
of Arthritis in Acne Fulminans and Acne Conglobata Total Patients Number (%)
AC Patients Number (%)
4 (14)
3 (20)
1 (7)
Cervical
6 (21)
6 (40)
0
Thoracic
4 (14)
3 (20)
1 (7)
11 (38)
9 (60)
2 (14)
14 (48)
11 (73)
3 (21)
Joint Involved
AF Patients Number (%)
Axial Sternoclavicular Spine
Lumbo-sacral Sacroiliac Appendicular Acromioclavicular
3 (TO)
2 (13)
1 (7)
Shoulder
1 (3)
1 (7)
0 0
Elbow
1 (3)
1 (7)
Wrist
6 (21)
4 (27)
1 (7)
Hip
7 (24)
4 (27)
3 (21)
Knee
11 (38)
3 (20)
8 (57)
Ankle
9 (31)
6 (40)
3 (21)
Subtalar
1 (3)
0
1 (7)
TarsaVlP
9 (31)
9 (60)
0
Abbreviations:
AC, acne conglobata; AF, acne fulminans.
Note. 33 of 60 total patients with musculoskeletal abnormalities associated with acne had arthritis (55%), but information on specific joint involvement was available for only 29 of these patients; therefore data are given as a percentage of these 29 patients. Fifteen of these 29 patients were classified as having AC, including 5 patients with the follicular occlusion triad, and 14 patients were classified as having AF.
250
KNITZER AND NEEDLEMAN
bone formation, and alignment abnormalities. Coarse paravertebral ossifications, hyperostoses, smooth anterior syndesmophyte formations with corner erosions and sclerosis, and calcified tendons also have been reported and are identical to those seen in seronegative spondyloarthropathies.3-5 Arthralgias are present in approximately one fourth of the AC patients and typically involve the elbows, hips, knees, ankles, and small joints of the feet.2’3’5A single AC patient had lytic bone lesions in the right ulna and fourth thoracic vertebrae.2 Muscle involvement is not a part of the musculoskeletal syndrome in AC or FOT. The course of the musculoskeletal disease in most AC patients is one of recurrent episodes of axial and peripheral joint arthritis or arthralgias, which may continue to occur for weeks to years after their initial presentation.3-5 It is unknown whether radiological abnormalities reverse to normal over time. THE AF-ASSOCIATED
MUSCULOSKELETAL
SYNDROME AF is the most aggressive and destructive form of acne. Affected individuals have a prior history of AV; the disease worsens acutely and is sometimes precipitated by viral illness,17,22 stress and fatigue,8X’8or institution of isotretinoin therapy.” The hallmark lesion of AF is an exquisitely tender, erythematous ulcer containing reddish-yellow gelatinous material covered by a friable hemorrhagic crust.‘sX48Cultures of skin lesions have grown Corynebacterium acnes, l5 staphylococcal species,‘z7x22Pityrosporon
ovale,” Propionibacterium acnes, ‘SOEscherichia coli, l4and proteus species.” On histologic exam-
ination, AF lesions show an intense polymorphonuclear infiltrate with invasion of the follicle wall, pronounced edema, and vascular hyperplasia with perivascular histiocytic and lymphocytic infiltrates.” Healing of the inflamed areas leaves extensive scarring. The onset of musculoskeletal symptoms in AF patients temporally coincides with the onset of AF. These patients are usually male, ages 13 to 22 years (median age, 16 years); only two of the reported cases have been female.7’3oNinetyeight percent of reported AF patients with musculoskeletal symptoms are white. Of
note, fever and weight loss are present in 100% of AF patients with musculoskeletal sympFever as high as 41°C has toms. ‘~‘~11~1*~15,16~‘8~2o,27 been reported.21 Weight loss may be dramatic, with documented losses of 12 kg occurring as quickly as 1.5 kg/wk.‘,‘* Patients with AF have a different spectrum of musculoskeletal abnormalities than patients with AC (Table 3). The most distinctive feature of the AF-associated musculoskeletal syndrome is the presence of painful bone lesions, found in 39% of patients. In approximately 50% of patients with bone lesions, multiple osseous defects are present,6~8~‘0~12S14’U.“.27~29 with as many as nine lesions reported in one patient.27 The bone lesions generally become painful at the time of the acne flare, although they may become symptomatic several weeks prior to the worsening of the skin condition.*l Asymptomatic bone lesions may also be present and account for about one quarter of all bone lesions. These asymptomatic lesions are detected when a radionuclide (99mTc)bone scan is performed to evaluate symptomatic lesions elsewhere. Bone scanning shows increased uptake of tracer in areas of both symptomatic and asymptomatic bone lesions. Radiographic evaluation of symptomatic bone lesions are abnormal in over 90% of cases and show lytic bone lesions12,21,23 or periosteal reaction.7’8 Most lesions are located in the clavicle, sternum, and long bones of the extremities (Table 5). These locations would be atypical for osteomyelitis, which, in this age group, characteristically occurs in the epiphyses of long bones and only
Table 5: Distribution
of Bone Lesions in the
Acne Fulminans Musculoskeletal Location
Syndrome
Number of Lesions 6 6
Clavicle Sternum Tibia
5
Humerus
4
Greater
trochanter
3
Ilium
3
Femur
2
Fibula
2
Note. One lesion has been reported in each of the following areas: cervical spine, thoracic spine, acromion,
ulna, carpal,
metacarpal, ankle, subtalar, tarsal, and metatarsal joints.
ACNE-ASSOCIATED
MUSCULOSKELETAL
251
SYNDROMES
rarely involves the clavicle.” Biopsies of the bone lesions have only yielded foci of chronic inflammation,19,21,23 marrow fibrosis,24 or normal tissue,‘* without evidence for infection. Patients with these bone lesions may have elevated serum alkaline phosphatase levels.14,‘9 Arthritis is present in one third of patients with the AF-associated musculoskeletal syndrome. The arthritis is usually nondeforming, self-limited, and has a predilection for the knees; 57% of AF patients with arthritis have involvement of this joint (Table 4). Arthritis of small joints occurs less frequently in AF patients than in AC patients. Sacroiliitis is also uncommon, occurring in only 7% of all AF patients with musculoskeletal abnormalities (Table 3) and in 21% of those AF patients who have arthritis (Table 4). Diffuse areas of demineralization’x’8 periosteal new bone formation, and transverse bands of radiolucency may be seen on radiographs of the joints.18 Biopsy of synovium from affected joints has shown only mild hyperplasia with moderate numbers of lymphocytes and plasmacytes.” Whereas frank arthritis is less common in the AF-associated musculoskeletal syndrome than in the AC-associated musculoskeletal syndrome, arthralgias and muscle involvement are more common (Table 3). Arthralgias are present in 80% of patients with the AF-associated musculoskeletal syndrome, with the hips and shoulders the most commonly involved sites. Myalgias also frequently involve the hip and shoulder girdles. Overt myositis has been reported in 3 of 41 (7%) AF cases with musculoskeletal symptoms, and, when present, has been uniformly accompanied by muscle weakness.8”h.‘9Although creatinine phosphokinase levels have been within normal limits,“,16in all 3 patients, electromyography has shown fibrillations and positive wave patterns consistent with myositis.R,16.‘9 In two patients with myositis, results of muscle biopsy showed scattered foci of muscle fiber necrosis associated with mononuclear cell infiltrates.16.19In one patient in whom myalgias and weakness were present and electromyography results were abnormal, the muscle biopsy was nondiagnostic. Because patients with the AF-associated musculoskeletal syndrome present with an acute
process including fever, weight loss, leukocytosis, and bone lesions, the possibility of sepsis or osteomyelitis is routinely raised. Exhaustive investigations for a nidus of infection other than the skin have been unrevealing. Blood cultures have been negative except for sporadic growth of propionibacterium and staphylococcal species thought to be contaminants.‘~11’14~18~21~22~24 Culture and microscopic examination of cerebrospinal and synovial fluids have been sterile.“.21 Bone biopsy specimens have been culture negative except in one case where P acnes was isolated.*’ The prognosis of patients with the AFassociated musculoskeletal syndrome is variable. With resolution of the initial acne flare, there may be immediate control of all musculoskeletal symptoms and no further problems despite subsequent acne exacerbations.” Bone lesions may resolve within 1 month of effective therapy and control of the acne.14 However, more commonly, there are episodes of arthritis, arthralgias, and myalgias, which may recur over many subsequent years.8~‘o~13~‘7~‘8 These recurrent episodes of musculoskeletal symptoms may accompany a flare of acne or may occur when the skin disease is under good contro1.18 In some patients, exacerbations of their musculoskeletal symptoms may be precipitated by the tapering of steroid therapy used to treat the underlying acne.8,29 THE ISOTRETINOIN MUSCULOSKELETAL SYNDROME IN ACNE PATIENTS
Isotretinoin is a synthetic derivative of vitamin A, used since 1976 with benefit in the treatment of cystic and congobate acne”4 and disorders of keratinization.54 In patients treated with isotretinoin for diseases other than acne, premature epiphyseal closure,3’ transient mild musculoskeletal symptoms,42 and symptomatic skeletal hyperostoses resembling diffuse idiopathic skeletal hyperostosis have been reported.33,55These abnormalities occur more frequently in patients treated with isotretinoin doses greater than 2 mg/kg/d or with continuous therapy over several years.” These side effects of isotretinoin are not unexpected, because vitamin A itself can cause bone and joint pain, calcifications in pericapsular ligaments3* and, in children, cortical thickening of tubular bones,
252
metaphyseal cupping and splaying, and premature fusion of the growth plate?“” Musculoskeletal abnormalities among patients taking isotretinoin for acne occur with equal frequency in males and females, whose ages range from 15 to 52 years. Diffuse myalgias and arthralgias are the most common musculoskeletal symptoms, occurring in 27% in one prospective study of 120 patients41 and “nearly all patients” in another prospective study of 96 patients.32 However, these myalgias and arthralgias are mild and resolve spontaneously within a few days, without discontinuation of the isotretinoin therapy.37 Skeletal hyperostosis is the next most common musculoskeletal abnormality associated with isotretinoin therapy for acne, occurring in 24 of 220 reported acne patients who were treated with isotretinoin and who subsequently developed musculoskeletal symptoms.32’41The hyperostoses tends to occur in the axial skeleton, especially the cervical spine.39 In the prospective study of Kilcogne et a1,32 10 of 96 patients developed small horizontal spurs extending from the anterior margin of one or more vertebral bodies. These spurs differ from those seen in diffuse idiopathic skeletal hyperostosis in their small size and lack of involvement at multiple levels of the spine. Spurs may develop as early as 6 months after initiation of isotretinoin therapy.32 The occurrence of these skeletal hyperostoses is not dose-related when isotretinoin is taken in doses less than 2 mg/kg/ d.32,41There is no correlation between radiographic changes and musculoskeletal signs or symptoms in these patients.32.4’It is not known if these hyperostoses undergo regression after cessation of treatment.39 Other isotretinoin-associated musculoskeletal abnormalities include soft tissue calcification of tendons and ligaments33’40and arthritis. One acne patient treated with isotretinoin developed a noncalcified Achilles tendonitis.37 Three patients developed arthritis.37,38In one patient with isotretinoin-induced arthritis, in whom a diagnostic arthrocentesis was performed, the synovial fluid white blood cell count was 2,3OO/uL with 90% polymorphonuclear leukocytes, and cultures were negative3’ in two of the three patients. The arthritis resolved quickly without sequelae and without stopping ther-
KNITZER AND NEEDLEMAN
apy.37,38In the third patient, the arthritis resolved shortly after isotretinoin was stopped and indomethacin was begun.37 Some patients, particularly those with AC, may be started on isotretinoin therapy when their acne flares. If these patients subsequently develop musculoskeletal complaints, the physician must determine whether these symptoms are related to the underlying acne or to the isotretinoin therapy. If the patient has severe or persistent arthralgias or myalgias, frank arthritis, or myositis, it is more likely that these complaints are related to the acne, rather than the isotretinoin therapy. LABORATORY
EVALUATION
Laboratory findings are similar in patients with either the AC-associated or the AFassociated musculoskeletal syndromes. Elevated erythrocyte sedimentation rates, leukocytosis including left shift and toxic granulations, and anemia are present in many patients. Thrombocytosis has been reported in one patient with AF.30 The severity, extent, and rapidity of the acne exacerbation seem to correlate with the degree of the laboratory abnormality. Hypergammaglobulinemia with a selective increase in immunoglobulin (1g)A or IgG,3,14Z16 or polyclonal increases in IgG, IgA, and IgM may occur.22 Renal function remains unchanged from baseline values, although urinalyses in some AF patients may show microscopic hematuria of unknown etiology.12,16,22’24 Antinuclear antibodies and IgM rheumatoid factors are not present in patients’ sera. Component C3 levels are decreased,” norma1,14~16~20~21~59 or increased,5g while C4 levels are norma1’4Z’6’20’21 or increased.“,59 Levels of circulating immune complexes are normal’ or elevated.3x25 When tested, delayed-type hypersensitivity skin test responses have been abnormal in most AC and AF patients with musculoskeletal symptoms, with no response to challenge with tuberculin, trichophyton, or dinitrochlorobenzene.aT62 In contrast, patients with AV or AC without musculoskeletal abnormalities respond to these same antigens.61 The significance of this finding is unknown. T cell proliferative responses have been normal when stimulated with the mitogen phytohemagglutinin or with purified protein There is a single report derivative antigen.6.61’63
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of uncharacterized “decreased T suppressor cell function.“24 Laboratory studies of patients with the isotretinoin-associated musculoskeletal syndrome do not show anemia, leukocytosis, or elevated erythrocyte sedimentation rates. However, serum triglycerides have occasionally been elevated.64 PATHOGENESIS
The original description of acne-associated arthritis by Burns and Coleville was one which suggested the presence of septicemia.’ This description may have fostered the hypothesis that infection was responsible for the musculoskeletal manifestations associated with acne. Although there have been isolated case reports of C acnes osteitis and osteomyelitis,52 the results of cultures in the vast majority of cases have not substantiated infection as a pathophysiological mechanism in the acne-associated musculoskeletal syndromes. Other investigators have speculated that the myalgias, bone lesions, and joint complaints may represent a “reactive arthritis.” It has been postulated that these musculoskeletal abnormalities represent a hypersensitivity response in susceptible individuals to sebum, bacterial antigens, or altered skin antigens.1r8.65In support of this process, Williamson et al have found that some AF patients develop an exaggerated area of induration with central necrosis and a surrounding erythematous flare in response to intradermal P awes antigen.26 Purvel has reported that patients with AC have increased lymphocyte proliferation in response to P acnes, but not to phytohemagglutinin.” In addition, some AC patients develop antibody against P acnes. 6
It has also been proposed that acne-associated musculoskeletal signs and symptoms reflect immune complex-mediated pathological events.25 This hypothesis is supported by the clinical findings of splinter hemorrhages,16 erythema nodosum,25zz6hematuria,12~16~1s~22~24 myositis, 8,16,‘9 diffise increases in serum y globulins,22 and steroid responsiveness.65 However, circulating immune complexes have been found only in those AP patients with musculoskeletal abnormalities who also have erythema nodosum.*’ Host factors in acne patients may contribute
to susceptibility toward musculoskeletal complications. There are two reports of monozygotic twins who developed virtually identical presentations of the AF-associated musculoskeletal syndrome within 2 months of each other.“,” HLA-B27 does not appear to be associated with the with development of the clinical picture of a seronegative spondyloarthropathy in AC patients. When tested, HLA-B27 antigen was absent in 13 of 14 AC patients. THERAPY
Therapy for the musculoskeletal syndromes associated with AC and AF consists of aggressive treatment of the underlying acne, combined with therapy for the musculoskeletal abnormalities themselves. Milder forms of acne may respond to topical or oral antibiotics. More severe disease often requires the addition of synthetic retinoids, particularly isotretinoin. If the above drugs are not effective in controlling the acne, local and systemic steroid preparations may be used. Other drugs which have been reported to be effective in severe acne include Dapsone (Jacobus Pharmaceutical Co, Inc, Princeton, NJ)16**land Clofazimine (CibaGeigy, Frolunda, Sweden).’ Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) may be useful in the control of low-grade fever, arthralgias, arthritis, and pain from bone lesions in patients with AC or AF.2,6,29 Monoarthritis or oligoarthritis may respond to intraarticular steroids.7 Most patients with the AF-associated musculoskeletal syndrome have been treated with systemic steroids because their high fevers, progressive weight loss, and joint inflammation were unresponsive to aspirin or NSAIDs. Prednisone, given in doses from 15 to 40 mg/d, has alleviated many of these symptoms within 12 to 72 hours.9,‘4 The myalgias and arthralgias associated with isotretinoin therapy are generally mild and transient and disappear spontaneously without stopping therapy. Similarly, frank arthritis may resolve with joint aspiration or NSAID therapy and not require discontinuation of isotretinoin. ACKNOWLEDGMENTS The authors thank Drs Barry Handwerger Anderson for their review of this manuscript.
and Regina
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