A Study of Musculoskeletal Manifestations in 12 Patients with SAPHO Syndrome Jeff P

Original Article

A Study of Musculoskeletal Manifestations in 12 Patients with SAPHO Syndrome Jeff P. Steinhoff, Ana Cilursu, Gerald F. Falasca, Leonardo Guzman, Antonio J. Reginato

Synovium and synovial fluid findings in SAPHO (synovitis, acne, pustulosis, with the syndrome (11–13). Most of hyperostosis, and osteitis) syndrome have not been well characterized, and only a the patients with SAPHO syndrome few patients have been described in the Americas. We describe clinical, pathologic, have been described in Japan, Scan- and synovial fluid findings in 12 patients with the SAPHO syndrome: hidradenitis dinavia, Germany, and France (14– suppurativa (7), acne fulminans or conglobata (3), acneiform folliculitis (1) and 17). Although both the SAPHO syn- palmoplantar pustulosis (1). Routine synovial fluid studies were performed in 6 drome acronym and classification patients, and light and transmission electron microscopic studies were performed criteria were proposed in 1987 by in synovium in 2 patients and in bone in 1. The most common musculoskeletal manifestations included erosive or Chamot et al. (8), these criteria have nonerosive oligoarthritis involving metacarpal phalangeal (MCP) and meta- not been validated in comparison tarsal phalangeal (MTP) joints as seen in 9 patients, sclerosis of the sacroiliac with closely related conditions, par- joints as seen in 5 patients, and osteitis pubis as seen in 1. Three patients had ticularly seronegative spondyloar- signs of skeletal hyperostosis. The patients with acne fulminans and acneiform thropathies. This syndrome still is folliculitis had chronic aseptic multifocal osteomyelitis. Synovial fluid was under-reported and possibly under- sterile in 7, mildly inflammatory in 5, and highly inflammatory in 2. Electron recognized in the Americas, likely microscopic studies of synovium in 2 patients and of bone in 1 were not useful because of its chronic and relapsing to detect microorganisms. Three African-American patients with hidradenitis nature as well as its expanding body suppurativa presented with pyoderma gangrenosum, and 2 of them had of clinical and radiographic manifes- leukocytoclastic vasculitis, and a life threatening course unresponsive to anti- tations. Musculoskeletal manifesta- biotics, corticosteroids and immunosuppressive therapy. tions have been characterized by the SAPHO in the Americas is most severe in African-Americans with hidradenitis suppurativa, and it presents with heterogeneous musculoskeletal and presence of acute or chronic synovi- cutaneous manifestations including erosive polyarthritis or oligoarthritis with tis, sacroiliitis, monostotic or polyos- nonspecific mild inflammatory fluid. Leukocytoclastic vasculitis and recalci- totic sclerosing bone lesion(s), and trant pyoderma gangrenosum were seen in 2 of our patients with the most sterile osteomyelitis (2, 4, 17–24). In- severe hidradenitis suppurativa. SAPHO syndrome may present with clinical manifestations similar to those seen with seronegative spondyloarthropathies, but it has distinctive cutaneous, radiographic articular, and bone manifestations. Sites of chronic infection need aggressive antibiotic therapy and may Department of Medicine, Rhode Island Hospital, The Miriam Hospital, Providence, Rhode Island, need surgical resection. (J Clin Rheumatol 2002;8:13–22) USA (JPS); Atlantic City Medical Center, Atlantic City, New Jersey, USA (AC); Cooper University Key words: SAPHO syndrome, Acneiform folliculitis, Hidradenitis suppura- Medical Center, Robert Wood Johnson School of tiva, Palmoplantar pustulosis, Acne fulminans, Acne conglobata Medicine, Camden, New Jersey, USA (GFF); Head Teaching Program, Division of Internal Medicine, Salvador Hospital, University of Chile, Santiago, Chile (LG); Professor of Medicine, Chief Rheuma- tology Section, Cooper University Medical Center, Robert Wood Johnson Medical Center, Camden New Jersey, USA (AJR). ince 1959, there have been PHO (synovitis, acne, pustulosis, hy- Address reprint requests to: Antonio J. Reginato, over 200 reports of patients af- perostosis, osteitis) syndrome (1–10). Professor of Medicine; Chief, Division of Rheuma- tology, Cooper Hospital/University Medical Cen- flicted with 2 or more of the Hidradenitis suppurativa and pyo- ter, Robert Wood Johnson School of Medicine, 401 S Haddon Avenue, Camden, NJ 08103. heterogeneous combination or re- derma gangrenosum are other skin Copyright © 2002 by Lippincott Williams & lated findings now referred to as SA- conditions that may be associated Wilkins, Inc.

Steinhoff et al. • Musculoskeletal Manifestations of SAPHO 13 formation about radiographic manifestations of peripheral joint and sy- TABLE 1. Diagnostic criteria for SAPHO syndrome novial fluid analysis in this condition is scarce (17). Spondyloarthropathies Sterile multifocal chronic osteitis: with or without associated inflam- Involvement of the chest, spine, pelvis or long bones matory bowel disease (10) have also Absence of skin lesions been reported in patients with the Acutea or chronic arthritisb associated with: syndrome, but the human leukocyte Palmoplantar pustulosis antigen (HLA) B-27 has been found Palmoplantar pustular psoriasis in only about 10% of such patients (11–14, 17). Because this syndrome is Severe acne not commonly observed in the Hidradenitis suppurativa c United States, and because there are Sterile mono or polyosteitis associated with: no validated criteria, patients with Palmoplantar pustulosis features of SAPHO present the po- Palmoplantar pustular psoriasis tential for misdiagnosis. In this re- Severe acne port, we describe a wide spectrum of Hidradenitis suppurativa relapsing, often disfiguring skin in- Folliculitis volvement, musculoskeletal syn- Modified from Chamot AM, Benhamou CL, Kahn MF, et al. Le dromes, and other systemic manifes- syndrome acne pustulose hyperostose osteite (SAPHO). Resultat de tations, as well as synovial fluid and une enquete national. 85 observations. Rev Rhum 1987;54:187–96. pathological findings of patients a Pseudo-septic; thought to suffer from SAPHO syn- b drome. with periarticular bone involvement; c with positive culture for Propionibacterium acnes. PATIENTS AND METHODS Twelve patients with features of SAPHO syndrome have been seen since 1974 at Cooper Hospital analysis performed by standard acne, acneiform folliculitis, palmo- University Medical Center, Cam- techniques in addition to culture for plantar pustulosis, and pyoder- den, New Jersey (8 patients), Vet- bacterial, fungal, and acid-fast ba- ma gangrenosum were performed erans Administration Medical Cen- cilli. Search for propionibacterium based on characteristic clinical and ter, Philadelphia, Pennsylvania acnes in aerobic or anaerobic cul- pathologic findings (26, 27). Labora- (2 patients), and Salvador Hospi- tures was not performed. Synovial tory testing included serum cal- tal, Santiago, Chile (2 patients). In tissue was obtained from the ankle cium, alkaline phosphatase, hemo- accordance with the diagnos- of patient 8 and the wrist of patient globin, hematocrit, white blood cell tic classification recommended by 2, and bone and synovium were count, erythrocyte sedimentation Chamot et al. (8) (Table 1), these taken from the left wrist of patient rate (ESR), rheumatoid factor (RF), patients presented with a wide va- 11. Tissues were fixed in formalin and antinuclear antibodies (ANA) in riety of musculoskeletal manifesta- and stained with routine stains. In most of the patients. Anticytoplas- tions, including chronic multifocal patients 2 and 11, synovium and mic, anticardiolipin antibodies, and sterile osteomyelitis, hyperostosis, bone, respectively, were also fixed in HLA-B27 testing was performed in and erosive and/or nonerosive pe- glutaraldehyde (1⁄2 strength Kar- only 4 patients. In patient 11, bone ripheral or axial arthropathies as- novsky’s fixative) and processed for scintigraphy and nuclear magnetic sociated with hidradenitis suppu- transmission electron microscopic resonance imaging were done to de- rativa (patients 1 through 7; Table studies in accordance with a previ- tect areas of bone involvement asso- 2), ulcerative or pustular forms of ously described technique (25). Sur- ciated with areas of clinical apparent acne or acne conglobata (patients 2, gical or punch out skin biopsies cellulitis. 5, 8, 9, and 10), acneiform folliculi- were performed in areas of hidrade- tis (patient 11), and palmoplantar nitis suppurativa (patients 1 through RESULTS pustulosis (patient 12; Table 3). 7), areas of pyoderma gangrenosum Patients were evaluated using (patients 1, 2, and 7), skin lesions Demographic Features conventional radiographic examina- with clinical features of vasculitis Eight patients were African- tion of the peripheral joints, pelvis, (patient 1 and 7), and acneiform fol- American, 2 were Latin-American, and axial skeleton. Arthrocentesis liculitis (patient 11). The diagnosis and 2 were Caucasians. Forty-five was performed in patients 1, 2, 3, 7, of hidradenitis suppurativa, acne percent were women. The age at 8, 10, and 11, with synovial fluid conglobata, ulcerative and pustular presentation of the articular com-

14 Journal of Clinical Rheumatology • Volume 8, Number 1 • February 2002 tihf tal. et Steinhoff

TABLE 2. Hidradenitis suppurativa and SAPHO syndrome • uclseea aiettoso SAPHO of Manifestations Musculoskeletal Acne Pyoderma Hidradenitis # Patient Conglobata Gangrenosum Suppurativa Miscellaneous Synovitis X-Ray Findings Treatment

1 50yoAW — L. Leg Groin L. hand pathergy R. wrist & ankle R. SI sclerosis Surgery, HS Bilateral keratitis Bilateral 5PIP & Erosive: hands: bilateral JSN of Prednisone Elevated ESR, DIP 1-3MCP Cephalosporins B-27 negative Feet: JSN of L. 2-4 PIP & R. 3-4 Ibuprofen PIP Acetaminophen Cupping of R. 1 MTP and L. 1 DIP 2 56yoAM Face GB Groin Elevated ESR L. wrist Osteopenia Surgery, HS R. Leg Axilla L. knee R. 1 MCP sclerosis Colchicine Neck Knee sclerosis & JSN Indomethacin Probenecid 3 33yoAW —— Scalp Elevated ESR Elbows, neck Periarticular osteopenia of wrists Surgery, HS Axilla L. wrist & PIPS and hands Cephalexin, ASA R. 4PIP Topical acetate 4 48yoAM —— Axilla Elevated ESR Bilateral L. iliac hyperostosis Surgery, HS Groin MCPs & PIPs SI sclerosis: L>R Indomethacin Rectum Feet: R. midtarsal erosion Bilateral MTP demineral. R. 1&5 PIP erosion 5 34yoCW Face — Axilla Elevated ESR Feet: PIPs & Hand demineralization Surgery, HS Groin R. second DIPS aJS of L. SI joint with mild Doxycycline digit-Raynaud’s sclerosis Minocycline R. foot NTP (Raynaud’s) hyperesthesia & skin dystrophy 6 46yoAW —— Groin L. uveitis Bilateral wrist & Periarticular demineral. of feet and Surgery, HS Polyclonal PIPs R. 4 MCP hands Erythromycin gammopathy R. SI sclerosis Tetracycline Elevated ESR ؉ Spine: Sclerosis of L5,S1 Sulfasalazine RF Ciprofloxacin Prednisone, NSAIDs 7 38yoAW — Feet Groin Axillary cellulitis Knees wrists Feet: hyperostosis Surgery, HS Ankles Axilla Polyclonal ankles elbows Erosion: L2&5MTP, bilateral Prednisone Hands Neck gammopathy cuboid&1MTP Methotrexate Culture: P. acnes Hands: erosion of R.5MCP and R. Antibiotics Elevated ESR, fifth digit flexion contr. Colchicine B27 negative Indomethacin A ϭ African-American; ASA ϭ aspirin; C ϭ Caucasian; DIP ϭ distal interphalangeal joint; ESR ϭ erythrocyte sedimentation rate; GB ϭ gall bladder; HS ϭ hidradenitis suppurativa; JSN ϭ joint space narrowing; L ϭ left; M ϭ man; MCP ϭ metacarpal joints; MTP ϭ metatarsal joint; NTP ϭ nitroglycerin paste; R ϭ right; RF ϭ rheumatoid factor; SI ϭ sacroiliac; W ϭ woman. 15 TABLE 3. Acne, acneiform folliculitis, palmoplantar pustulosis, and SAPHO syndrome

# Patient Skin Lesion Miscellaneous Synovitis X-Ray Findings Treatment

8 33yoAM Acne conglobata Elevated ESR L. knee Bilateral knee Tetracycline B27(؊) demineralization ASA Hyperostosis: cervical spine, bilateral sacrum and ilium Hands: erosion of ulnar styloid and L.2PIP osteolysis Feet: Erosion of R. 4PIP Cerv. Spondyloarthropathy 9 17yoLAM Acne Fulminans Fever R. ankle Periostitis, osteolytic. Tetracycline Elevated ESR. lesion of R. fibula Drainage (B27(؊ Leukocytosis 10 20yoLAM Acne Fulminans Fever Knees Bilateral SI erosions Tetracycline Elevated ESR NSAIDs Leukocytosis 11 43yoCM Acneiform Mouth ulcers R. knee Osteitis (by MRI) Antibiotics folliculitis Cellulitis, fever Ankles NSAIDs Elevated ESR (Episodic) 12 60 BW Palmoplantar Elevated ESR Dactylitis Localized demineralization NSAIDs Phalanges Corticosteroids A ϭ African-American; ASA ϭ aspirin; C ϭ Caucasian; ESR ϭ erythrocyte sedimentation rate; JS ϭ joint space; JSN ϭ joint space narrowing; LA ϭ Latin-American; M ϭ man; SI ϭ sacroiliac joint; R ϭ right; W ϭ woman.

plaints for the 12 patients ranged Vasculitic manifestations. Patient ceral manifestation of pyoderma from 17 to 63 years of age, with a 1 developed severe hidradenitis sup- gangrenosum. His cholecystitis median age of 45 years (Tables 2 purativa associated with pyoderma and acute abdomen resolved with and 3). Patients with hidradenitis, gangrenosum of her thigh, biopsy corticosteroid therapy. Patient 7 acne, and palmoplantar pustulosis proven vasculitic lesions on her legs developed extensive pyoderma are discussed. (Fig. 1B), bilateral keratitis, and gangrenosum associated with se- pathergy. She also presented with vere recalcitrant biopsy-proven Hidradenitis Suppurativa groin, vulvar, and perirectal ab- leukocytoclastic vasculitic lesions Seven of the 12 patients with scesses requiring repeated surgical of the legs and pyoderma gangre- SAPHO syndrome presented with drainage and extensive resection of nosum of her hands and feet, hidradenitis suppurativa. All even- her perineal sweat glands and rec- which were only partially con- tually required surgery for drain- tum, culminating in a permanent co- trolled with antibiotics, methotrex- age and/or resection of the sweat lostomy (Fig. 1A). Her vasculitic le- ate, dapsone, and cyclosporine. glands. Two of these also had acne sions and pyoderma gangrenosum Musculoskeletal features. Articu- conglobata. Six were African- did not respond to hyperbaric lar manifestations became appar- American, and 5 were women. The age at presentation of the articular oxygen, local application of anticho- ent roughly 1 to 5 years after the complaints for these 7 patients linergics, high-dose and pulse corti- hidradenitis suppurativa was diag- ranged from 33 to 56 years of age, costeroid therapy, or cyclophospha- nosed. Joint involvement, affecting with a mean age of 43 (Table 2). mide. She died due to complications mainly wrists, fingers, and toes Groin areas were affected in all 7 of a Gram-negative bacteremia. Pa- (proximal interphalangeal (PIP), patients (Fig. 1A), axillae in 6, peri- tient 2 developed hidradenitis sup- MCP, and MTP joints), was seen in rectum and neck in 2, and breasts purativa of his groin, axillae, and 5 patients. Patient 2 presented with in 1. Three African-Americans pre- posterior neck, a large right-leg ul- a recurrent chronic synovitis of the sented with aggressive pyoderma cer with features of pyoderma gan- left wrist that required a synovial gangrenosum (Fig. 1B), and life- grenosum, and an acute abdomen biopsy and bacterial cultures to ex- threatening complications were ob- due to acalculous necrotizing cho- clude a chronic infectious etiology. served in 3. lecystitis, probably caused by a vis- Knee involvement was seen in 2

16 Journal of Clinical Rheumatology • Volume 8, Number 1 • February 2002 FIGURE 1. (A) Extensive scarring due to hidradenitis suppurativa of the groin and external genitalia was observed in patient 1. (B) Patient 1 also developed pyoderma gangrenosum of her left thigh and leukocytoclastic vasculitic lesions of both of her legs.

patients. Four patients had mild in- Laboratory and pathologic studies. Propionibacterium acnes from a cul- termittent back pain, with morning Clear synovial fluid was obtained ture of her pyoderma gangrenosum. stiffness lasting less than 30 min- from the right knee of 3 patients, Management. The articular utes. which showed normal viscosity and manifestations were easily con- Radiographic features. Periartic- 800–1000 cells/mm3 with 80% trolled with nonsteroidal anti-in- ular demineralization of affected mononuclear cells. No crystals were flammatory drugs (NSAIDs), but finger joints was seen only in 4 pa- seen, and cultures showed no bacte- the pyoderma gangrenosum and tients. Erosions in hands and feet rial growth. Serum protein electro- vasculitic skin lesions observed in 2 were seen in 3 patients in associa- phoresis revealed a polyclonal gam- patients were only partially con- tion with the most severe hidrade- mopathy in 2 patients. Synovial trolled with antibiotics, corticoste- nitis suppurativa, and 2 of those biopsy of the left wrist of 1 patient roid therapy, and immunosuppres- patients also had pyoderma gan- showed diffuse synovial lining sive therapy (Table 2). grenosum. In 2 patients, erosions cell proliferation, hyper vasculariza- extended deep into the subchon- tion, few macrophages, and abun- Acne Conglobata, Acne dral bone and had an overhanging dant perivascular lymphocytic and Fulminans, Acneiform edge, although the articular joint plasma cell infiltration (Fig. 3A). Folliculitis, and Palmoplantar space was preserved (Figs. 2A, B). Electron micrographs showed syno- Pustulosis Three patients had unilateral sub- vial cell proliferation, prominent en- Six patients presented with se- chondral sclerosis of the sacroiliac dothelial cells containing dense vere forms of acne and musculo- joint mainly affecting the iliac bodies, and perivascular infiltrates skeletal manifestations (Tables 2 bone, and 1 patient had both sacro- of lymphocytes, monocytes, and and 3). Two were African-Ameri- iliac joints affected with joint space plasma cells. No bacteria were seen can, 2 were Latin American, and 2 narrowing and subchondral sclero- (Fig. 3B). RF and ANA were nega- were Caucasian. Five were men. sis. One patient also demonstrated tive in all but 1 patient. HLA B-27 Two patients also had hidradenitis sclerosis and erosive changes of the testing was performed in 2 patients suppurativa and are included in symphysis pubis. and was negative. One patient grew Table 2.

Steinhoff et al. • Musculoskeletal Manifestations of SAPHO 17 with the antibiotic therapy and nonsteroidal anti-inflammatory agents. Another patient also had severe ulcerative acne (Fig. 5A) and presented with acute arthritis of his left ankle, high fever, and leukocytosis. Synovial fluid obtained was cloudy, with 30,000 cells/mm3 with 80% polymorphonuclear cells, negative gram and acid-fast stains, and eventual sterile bacterial cultures. Left ankle radiographs showed a round focal osteolytic area with a periosteal reaction of the distal fibula (Fig. 5B). A biopsy revealed a fibrotic synovium with scarce polymorphonuclear cell in- filtrate, necrotic bone fragments, and subsequent sterile bacterial cultures (Fig. 6). His acne re- sponded to antibiotic therapy, but his left ankle synovitis had a very chronic course while receiving antibiotics. It was finally controlled with the administration of indomethacin. Acneiform folliculitis. Acneiform folliculitis was observed in patient 11, a 43-year-old white man who since age 34 has presented with recurrent attacks of synovitis that mainly involves the right knee and ankles but sometimes migrated to other joints. His attacks were associated with high fevers that lasted 7–10 days. These attacks occurred FIGURE 2. (A) Articular erosions (arrow) observed in patient 1. (B) Erosion 2–3 times a year. On these occa- (arrow) seen in patient 7. Both patients had hidradenitis suppurativa and sions he also presented with peri- SAPHO. articular swelling of his thighs, knees, and ankles that was diag- nosed as cellulitis. He also had fol- Acne conglobata. One patient arthritis with indomethacin, but liculitis of his buttocks and legs had acne conglobata and developed his spondyloarthropathy showed since the beginning of his muscu- asymmetric polyarthritis involving progressive erosive radiographic loskeletal complaints. Serial bone his hands, knees, and feet in addition changes. His synovial fluid was scans revealed increased uptake in to a progressive erosive cervical mildly inflammatory with 5,000 his midtarsal and metatarsal joints, spondyloarthropathy with osteoscle- cells/mm3 with 80% mononuclear right ankle, right distal radius, left rosis of his cervical vertebrae and his cells. distal third of the ulna, right lateral sacroiliac joint (Fig. 4A). Joint ero- Acne fulminans. One patient pre- femoral condyle, and both tibial sions were seen in his ulnar styloids sented with ulcerating pustular acne, shafts. MRI of the left distal radius and several proximal interphalan- polyarthralgia, low back pain, high and both femurs showed an abnor- geal (PIP) joints. He also developed fever, and leukocytosis with radio- mally high central marrow signal an aseptic destructive arthropathy of graphic and scintigraphic changes of surrounded by low intensity areas his right second toe PIP joint (Fig. bilateral sacroiliitis. His acne was on T1-weighted pulse sequences 4B). His acne was partially con- controlled with tetracycline, and his and opposite signal characteristics trolled with tetracycline and his articular manifestations subsided on T2-weighted sequences, which

18 Journal of Clinical Rheumatology • Volume 8, Number 1 • February 2002 mation. Synovium revealed increased fibrosis with areas of neo- vascularization. Bacterial and mycobacterial cultures showed no growth. Acid fast, Gram, and silver stainings were negative. Electron microscopic studies showed increased osteoclasts with numerous large intracytoplasmic vacuoles. No microorganisms were seen. Laboratory studies showed an ESR of 89 mm/hour, a C-reactive protein of 114 IU. Serum biochemical profile, C3, C4, ANA, RF, anti- streptolysin O (ASO) titers, hepatitis B, hepatitis C, Lyme serologies, cryoglobulin, and rapid plasma re- gain (RPR) were negative. Enzy- matic testing for glucocerebroside leukocyte enzymatic activity was normal, and DNA studies for chro- mosome 16p13 locus for familial Mediterranean fever were uninfor- mative. Since the beginning of his attacks, the patient noticed erythem- atous papules and follicular pustules over his shoulders, proximal extremities, and buttocks. Skin biopsies obtained from several of these papules and pustules showed collections of polymorphonuclear cells in the hair follicles forming abscesses. Biopsies obtained from 2 different cellulitic areas showed signs of acute inflammation with perivascular inflammatory infil- FIGURE 3. (A) Left wrist synovium of patient 2 revealed slight synovial lining trates. Bacterial cultures showed no cell. proliferation, hypervascularization, and perivascular plasma cell and lympho- growth. A variety of nonsteroidal ϫ cyte infiltration. H & E 200. (B) Electron micrograph demonstrated endothelial anti-inflammatory agents as well (ED) synovial cells with flaps (F) and disrupted cell basement membranes (BM). as antibiotics and colchicine failed No evidence of organisms was seen. RBC ϭ red blood cell; P ϭ Pericytes. to control or alter the frequency of his attacks, although all were self- limited. Since 1993, only mild fol- was interpreted as possible aseptic cloudy fluid was aspirated from liculitis has been present, and he bone necrosis. his right ankle, which showed has experienced only intermittent His most recent episode was 5,000 cells/mm3 with 85% lympho- episodes of polyarthralgias with characterized by synovitis of his cytes and 15% polymorphonuclear occasional polyarthritis, which left first and fourth MCP joints and cells. No crystals were seen, Gram have been controlled with ibupro- ankles and a cellulitic area over his stain and acid-fast bacterial stain fen. left lateral malleoli. Bone scan were negative, and subsequent Palmoplantar pustulosis. One pa- showed increased uptake in his bacterial cultures showed no tient presented with a 2-month his- first and second left metacarpal growth. tory of painless hyperkeratotic bones and in both ankles, whereas A bone biopsy of his left second papules on her palms and soles those areas that had shown in- metacarpal bone showed a low- without evidence of skin psoriasis. creased uptake on previous bone grade chronic osteomyelitis with She also complained of diffuse scans were fading. About 5 mL of reactive fibrosis and new bone for- painful fingers and knees. Hand ra-

Steinhoff et al. • Musculoskeletal Manifestations of SAPHO 19 (Table 2). Leukocytoclastic vasculitis in hidrosadenitis suppurativa is unusual and may be coincidental or related to the persistent infectious agent antigens attacking the sweat glands. In our series, patients with both hidradenitis suppurativa and pyoderma gangrenosum had more aggressive manifestations. The patients with the most severe hidradenitis suppurativa had more erosive arthropathy than the patients with milder hidradenitis suppurativa (Table 2). Although pyoderma gangrenosum is sometimes associated with rheumatoid FIGURE 4. (A) Erosive spondyloarthropathy and increased bone density of the arthritis (30), inflammatory bowel cervical spine was seen in patient 8. (B) Patient 8 demonstrated a destructive disease (33, 34), and various spon- arthropathy of the right second toe PIP joint. dyloarthropathies (33, 34), there is only one report of visceral pyoderma gangrenosum (35). Patient 2 diographs showed demineraliza- articular demineralization, and is probably the first report of a SA- tion of her left second and fifth and spinal disease have been well-doc- PHO patient with hidradenitis sup- right fifth fingers, affecting the umented (11, 13, 16–17) and were purativa complicated with noncal- proximal and distal phalanges with present in our patients. The out- culous acute cholecystitis, possibly periosteal thickening. Her articular come in our patients differs from due to a visceral manifestation of manifestations failed to improve those described in a recent report pyoderma gangrenosum or vascu- with nonsteroidal anti-inflamma- from France that included 120 pa- litis. To our knowledge, patient 1 is tory agents, and she required a tients with SAPHO syndrome asso- also the first report of pathergy as- prolonged course of low dose cor- ciated with palmoplantar pustulo- sociated with hidradenitis suppu- ticosteroids and intensive hand oc- sis (50%), skin psoriasis (25%), rativa-SAPHO and pyoderma gan- cupational therapy. severe acne (9%), or even patients grenosum. without skin lesions (16%) ob- Other less common manifesta- DISCUSSION served in a population mainly tions, such as concomitant pyo- In assessing our clinical popula- formed by European whites (17). derma gangrenosum, acne con- tion, we compared the SAPHO man- All these patients had a benign globata, Raynaud’s phenomenon, ifestations of hidradenitis suppura- course without serious or life- sclerodactyly, and ocular manifesta- tiva, acne conglobata, palmoplantar threatening clinical or laboratory tions have been previously reported pustulosis, acneiform folliculitis, abnormalities, and most of the pa- (11, 15, 17) with hidradenitis suppu- ulcero-pustular acne, and pyoderma tients had a satisfactory response rativa-SAPHO. The histology of the gangrenosum with other reports (5– to nonsteroidal anti-inflammatory cutaneous and osseous manifesta- 17). We found that SAPHO associ- agents. A minority required ad- tions of SAPHO syndrome have ated with hidradenitis suppurativa ministration of second line drugs. been described previously (3, 17–21, was not entirely a disease of African- There were no deaths. All of our 29). However, there have been no American men as previously sug- patients with hidradenitis suppu- synovial membrane studies. gested by other studies (11, 21). Only rativa underwent extensive sur- Our studies of synovium re- 2 of our 7 patients were African- gery to remove areas of hidrosade- vealed a striking plasma cell infil- American men, far less than the 85% nitis and sweats glands, and trate, few macrophages, and gran- in earlier studies. There is clearly a received antibiotics and nonsteroi- ular dense deposits on electron high prevalence in the African- dal anti-inflammatory agents. The microscopy that are suggestive of American population, but African- 2 hidradenitis suppurativa patients immune complex deposition, pos- American women and Caucasians with associated vasculitis and pyo- sibly in response to bacterial anti- are also affected. derma gangrenosum received high gen presentation; however, no The musculoskeletal and ra- doses of corticosteroids, cyclophos- immunohistochemistry was per- diographic changes such as perios- phamide, or cyclosporine without formed. Immune complex forma- titis, hyperostosis, sacroilitis, peri- significant improvement (27–32) tion could be an important factor in

20 Journal of Clinical Rheumatology • Volume 8, Number 1 • February 2002 ports of SAPHO syndrome (Fig. 4A). Two patients presented with episodes of acne fulminans consist- ing of high fevers, leukocytosis, high ESR, and sterile osteolytic lesions in addition to periosteal reactive changes (Fig. 6). Their ages and clinical courses are also similar to previous reports of acne fulminans and SAPHO (12, 16, 22). To our knowledge, patient 11 is the first case of SAPHO syndrome associated with acneiform folliculitis. Patient 11 was a middle-aged Caucasian man with a chronic, intermittent, occasionally episodic migra- tory, periarthritis, cellulitis, and synovitis whose clinical manifestations also involved fevers and chills. These symptoms were in addition to chronic folliculitis and acneiform pustules on nonplantar skin regions. Bone biopsies revealed a sterile, low- grade osteitis and periostitis with inflammation and reactive fibrosis. Synovial biopsies demonstrated chronic synovitis, and skin biopsies demonstrated perifollicular abscess formation. In 4 patients with SAPHO syndrome in this series in whom HLA- B27 was studied, the test was negative. This finding corresponded with other previous studies (11, 12, 15, 17), which may reflect the low frequency of the B27 antigen in Af- FIGURE 5. (A) Ulcerating acne was observed in patient 10, who presented with rican-American patients, although acne fulminans. (B) Left ankle of patient 10 demonstrated periostitis of the distal several studies have cited a 5%– fibula and a focal osteolytic area (arrow). 10% incidence of HLA-B27 antigen (17, 19, 21). Most studies, including this the synovitis and erosive polyar- nance of polymorphonuclear cells one, have found few if any patients thropathy seen in our patients, but or lymphocytes, respectively. No who were positive for ANA, al- this would require further docu- Reiter’s cells were seen. Synovial though 1 study found 30% of pa- mentation. fluid analysis was important to ex- tients with a positive ANA test Synovial fluid obtained from 4 clude a septic or crystal induced (21). A novel finding in our series is patients with hidradenitis suppu- arthritis, but did not provide any the polyclonal gammopathy seen rativa was mildly inflammatory characteristic changes. in patients 6 and 7 associated with and showed a predominance of Severe forms of acne and mus- dense plasma cell infiltrates in skin mononuclear cells in 3 and poly- culoskeletal manifestations have and synovial biopsies (Fig. 3A). Al- morphonuclear cells in 1. Synovial also been frequently described (3, though increased plasma protein fluid was inflammatory in the pa- 6, 8, 12, 22). One patient with acne concentrations have been docu- tient with acneiform folliculitis and conglobata was radiographically mented, only 1 study has cited el- aseptic osteomyelitis of the ankle, afflicted with periarticular bone evated globulins, and subsequent as in the patient with acneiform demineralization, severe erosive serum protein electrophoresis folliculitis, with cell count of 5000 spondyloarthropathy, and spinal proved them to be ␣-globulins (12). and 30,000/mm3 and a predomi- hyperostosis similar to previous re- The exact mechanism involved

Steinhoff et al. • Musculoskeletal Manifestations of SAPHO 21 14. Sonosaki H, Mitsui H, Miyanaga Y, et al. Clin- ical features of 53 patients with pustulotic artro-osteitis. Ann Rheum Dis 1981;40:547–53. 15. Sonosaki H, Kawahima M, Hongo O, et al. Incidence of artro-osteitis in patients with pustulois palmaris et plantaris. Ann Rheum Dis 1981;40:554–7. 16. Bolukbas N, Bolukbas S, Erel A, et al. SAPHO syndrome associated with acne fulinans and prominent acromioclavicular joint involvement. Scand J Rehumatol 1996;25:180–2. 17. Hayem G, Boochaud-Chabot A, Benali K, et al SAPHO Syndrome. a long term follow up study of 120 cases. Semin Arthritis Rheum 1999;29:159–71. 18. Kasperczyk A, Fretschmidt J. Pustulotic ar- throosteitis: spectrum of bone lesions with pustulosis palmaris et plantaris. Radiology 1994;191:207–11. 19. Ralston SH, Scott PDR, Sturrock RD. An unusual case of pustulotic arthro-osteitis affecting the leg, and erosive polyarthritis. Ann Rheum Dis 1990;49:643–5. 20. 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