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SPONDYLARTHOPATHIES

The SAPHO SyndromeMinhchau Thi Nguyen, MD,* Andrea Borchers, PhD,*

Carlo Selmi, MD,*,† Stanley M. Naguwa, MD,* Gurtej Cheema, MD,*and M. Eric Gershwin, MD*

Objective: To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, andgenetics of the syndrome known under the acronym of SAPHO for Synovitis, Acne, Pustulosis,Hyperostosis, and Osteitis to heighten awareness of this entity.Methods: We conducted a Medline search using SAPHO syndrome, chronic recurrent multifocalosteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles fromthe retrieved references.Results: The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticulardisorders that are frequently accompanied by dermatoses characterized by neutrophilic pseudoab-scesses, but can also occur in isolation. SAPHO syndrome is rare, although probably underrecog-nized because its diagnosis may be challenging because of the wide variability in its musculoskeletaland cutaneous manifestations. This is especially true when atypical sites are involved and whenspecific skin lesions are absent. There are no standardized treatment protocols available. Currenttreatments are empirical and have the objective of providing relief from the at times debilitatingpain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs andanalgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs,biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have allbeen beneficial in some patients, but ineffective in others. This suggests that the pathogenesis ofSAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteriaand immunological dysfunction are hypothesized to play a role.Conclusions: The early recognition, diagnosis, and prompt treatment of SAPHO syndrome canprevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly allevi-ating pain in a majority of affected patients.© 2012 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 42:254-265

Keywords: synovitis, acne, pustulosis, hyperostosis, osteitis

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Starting in the 1960s, there have been reports of anassociation between cutaneous manifestations, inparticular palmoplantar pustulosis (PPP), pustular

soriasis, hidradenitis suppurativa, and severe acne (ful-inans or conglobata), with certain osteoarticular mani-

estations like peripheral synovitis or aseptic osteitis af-ecting the anterior chest wall and other skeletal sites.ince then, more than 50 designations have been used to

*Division of Rheumatology, Allergy and Clinical Immunology, University of Cali-fornia, Davis.†Clinical Immunology, IRCCS Istituto Clinico Humanitas, Milan, Italy.

Address reprint requests to M. Eric Gershwin, MD, Division of Rheumatology, Allergyand Clinical Immunology, University of California, Davis School of Medicine, 451

uHealth Sciences Drive, Suite 6510, Davis, CA 95616. E-mail: megershwin@cdavis.edu.

254 0049-0172/12/$-see front matter © 2012 Elsevier Inc. All rights reservedhttp://dx.doi.org/10.1016/j.semarthrit.2012.05.006

escribe these combinations, the more common oneseing pustulotic arthro-osteitis, sternocostoclavicularyperostosis, acne-associated spondyloarthropathy, ac-uired hyperostosis syndrome, or chronic recurrent mul-ifocal osteomyelitis. A group of French researchers, sus-ecting that these disorders might share commonharacteristics, conducted a national investigation of suchases (1). Their results indicated that a specific type ofone involvement, namely inflammatory osteitis with hy-erostosis, constituted a common denominator and ex-ibited the same characteristics whether accompanied byermatologic manifestations or not. These bone lesionsre mainly localized in the anterior chest wall, but maynvolve any skeletal segment (2). As a unifying concept,he French researchers proposed to group these disorders

nder the acronym SAPHO (originally Syndrome Acne

.

M.T. Nguyen et al. 255

Pustulosis Hyperostosis Osteitis, the “S” being changed toSynovitis the following year) (1,3). Even though pustulardermatoses originally appeared to be the unifying ele-ment, their presence is not absolutely required because (1)the typical osteoarticular manifestations are identical inthe absence or presence of cutaneous involvement and (2)it has since become more fully appreciated that dermato-logic manifestations can occur years before bone lesionsand may have been forgotten, but can also develop longafter the osteoarticular lesions.

Note that the original description of the SAPHO syn-drome and the inclusion criteria proposed for this entityspecifically include cases of chronic recurrent multifocalosteomyelitis (CRMO) (1,3). This condition was first de-scribed by Giedion et al. in 1972 (4) under the name ofsubacute and chronic symmetrical osteomyelitis, andmost frequently affects children, but has been reported inadults (5-8), whereas typical manifestations of SAPHOsyndrome have been described in children (9). There stillis some debate over whether CRMO represents the pedi-atric form of SAPHO or constitutes a separate entity.However, CRMO exhibits all the essential features of theSAPHO syndrome, including osteitis; hyperostosis; andthe association with skin disorders such as PPP, severeacne, pyoderma gangrenosum, and, in rare cases, Sweetsyndrome—although in a lower proportion of cases(�30% compared to 50% to 85% in adults). In addition,CRMO-like SAPHO syndrome is associated with inflam-matory bowel disease (IBD) (10-13). However, CRMOmost frequently affects the metaphyses of tubular bones,whereas other forms of SAPHO syndrome most ofteninvolve the axial skeleton, particularly the anterior chestwall. CRMO can affect the sternocostoclavicular region,but this generally manifests as hyperostosis of the medialend of the clavicle and, unlike in adults, spares other ele-ments of this region, including the sternoclavicular joint(14). Nonetheless, in the following, CRMO is considereda subtype of the SAPHO syndrome that affects childrenmuch more frequently than adults.

SAPHO syndrome is generally considered to be a rarecondition, possibly due to being underdiagnosed. A prev-alence estimate of �1/10,000 is frequently mentioned,although it is unclear what this is derived from becausethere are no actual data. Based on long years of experiencewith SAPHO, a German rheumatologist and SAPHOexpert estimates its prevalence to lie somewhere betweenthat of systemic lupus erythematosus and scleroderma andprovides a figure of 0.04% (ie, 40/100,000) (15). In theoriginal collection of French SAPHO cases overall, thegender distribution was approximately equal (1). Sincethen, the majority of cohorts comprising more than 20patients were characterized by a female preponderance,including various patient groups from France, Italy, andJapan (16-20), as had already been noted in an earlierdescription of pustulotic arthro-osteitis (21). An excep-tion is a Spanish cohort, for which equal numbers of men

and women were reported (22). The SAPHO syndrome

may present at any age but is most commonly seen inchildren and young to middle-aged adults (16,17).

CLINICAL PRESENTATION

The osteoarticular involvement is generally insidious inonset, but eventually patients will present with pain that isfrequently dramatic and incapacitating and may be exac-erbated by movement or application of pressure. Soft tis-sue swelling, often with redness and heat, and limitationof motion at the affected skeletal site(s) are other present-ing signs. Morning stiffness is quite frequently reportedranging in severity from mild to lasting several hours, andin cases of long bone involvement, a limp may be evident.Of note, quite a few cases of CRMO were preceded bytrauma (23-26). Systemic manifestations are uncommon;however, fever is sometimes reported and modest eleva-tions of erythrocyte sedimentation rate or C reactive pro-tein are common.

In adults, the most commonly affected skeletal site isthe anterior chest wall (65% to 90%, Table 1), followedby the spine (in �30%), with the thoracic spine beingmost frequently affected, followed by the lumbar andthen the cervical spine (2,27). Sacroiliitis is seen in up to13% to 52% of patients with SAPHO syndrome (2,27).The appendicular skeleton is not a frequent localization inadults with SAPHO syndrome, with 5% to 10% of themshowing involvement of the long bones, and 1% to 10%of patients experiencing mandibular lesions. In contrast,long bones represent the most frequent site of involve-ment in children, where the distal and proximal tibia aremost commonly affected, followed by the proximal anddistal femur (10,14,23,28). Lesions of spine, clavicle, pel-vis, and other sites are reported with highly variable fre-quencies. In both adults and children, there can be arthri-tis of the articulations adjacent to bone lesions, ie, theanterior chest wall and sacroiliac joints in adults, the an-kles and knees in children (10,23,28). Synovitis in periph-eral joints distant from the sites of bone involvement isseen in �30% of adults, but more rarely in children (10).

Skin manifestations may be evident at the time of pre-sentation with osteoarticular symptoms, but may haveoccurred years earlier or may develop later. In an earlydescription of 53 cases, skin involvement occurred withinan interval of 2 years before or after the onset of rheuma-tological symptoms in 70% of cases (21), but delays of upto nearly 4 decades have been reported (16,21,29). In thelargest cohorts described to date, skin involvement pre-ceded musculoskeletal symptoms in 40% to 68% of pa-tients, occurred simultaneously in �30% of patients, andmanifested later in 32% to 60% of cases (16,17,22). Atleast 15% of adults and more than 70% of children maynever experience skin lesions, whereas others may exhibit2 or even 3 different ones. The cutaneous lesions are neu-trophilic dermatoses. The most common one is PPP, rep-resenting 50% to 75% of all dermatologic manifestations

(Table 1) and affecting close to 60% of patients with

psoria

256 The SAPHO syndrome

extended follow-up (16,17). Of note, many pathologistsfeel that PPP cannot be distinguished unequivocally frompustular psoriasis, and it has become customary to sub-sume both entities under pustulosis or PPP. There is stillsome debate over whether psoriasis vulgaris should beincluded among the dermatologic manifestations ofSAPHO. Although it may represent up to one third of allskin involvement, it is frequently seen in combinationwith PPP or severe acne and occurs in isolation in only 5%to 10% of cases. Severe acne, ie, acne conglobata andfulminans, affects approximately one fourth of patientswith SAPHO syndrome, with men clearly predominating(1,16). Hidranetitis suppurativa (also called acne inversa)is considered to be a severe form of acne by some and torepresent a distinct entity that resembles acne by others. Itmainly affects women, yet men predominate among thecases of SAPHO syndrome that have been reported inassociation with hidradenitis suppurativa (30-32). Afri-

Table 1 Frequency of Clinical Manifestations in SAPHO Pat

Reference (1

Country Francen 12Age at diagnosis (mean, range) 37.7 (Male/female 50Years of study 1974Follow-up (yr) Mean 4.

1-23)Anterior chest wall involvement (%) 6Inflammatory back pain (%) NSpinal (%) 3Sacroiliitis (%) 4Long bones/peripheral (%)Mandible (%) 1Peripheral arthritis (%) 3Cutaneous manifestations (N/%) 110 (Of those (in %)

PPP overall �58Severe acne overall 2Psoriasis vulgaris overallPPP, isolated 3PPP � psoriasis vulgaris 2PPP � severe acne

PPP � hidradenitis suppurativaPsoriasis vulgaris, isolated 1Severe acne, isolated 2Severe acne � hidradenitissuppurativa

Other manifestationsInflammatory bowel disease (n/%) 9Of those Crohn’s disease 6/9Of those ulcerative colitis 3/9HLA-B27 (%) 1

NA, not available; PPP, palmoplantar pustulosis.aMedian and interquartile range.bCannot be determined exactly from the data provided because soand/or PV were reported.cThis figure is for the combination of severe acne with PPP and/or

can Americans appear to be particularly susceptible.

Other rare cutaneous manifestations of the SAPHO syn-drome include pyoderma gangrenosum and Sweet’s syn-drome (17,33-35). Skin involvement is not as frequent inchildren compared to adults.

RADIOLOGY

Radiography

Two of the osteoarticular manifestations of SAPHO syn-drome are hyperostosis and osteitis, which are chronicinflammatory reactions involving the cortical and medul-lary bone. In the initial stages of the disease, radiographsof affected areas are often normal. Early lesions are oftenpurely osteolytic with or without a sclerotic margin, typ-ically accompanied by an endosteal or periosteal reaction(14). With disease progression, these lesions becomemixed lytic/sclerotic or entirely sclerotic (14). Chronic

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M.T. Nguyen et al. 257

ing accompanied by narrowing of the medullary canal andenlargement of trabeculae.

Anterior Chest Wall

Anterior chest wall lesions can involve any component ofthe sternocostoclavicular region. Lesions usually developin 3 stages: stage 1 is localized to the area of the costocla-vicular ligament and may manifest as a primary en-thesopathy; in stage 2, an arthropathy of the sternoclavic-ular joint develops with osteolytic and osteoscleroticchanges of the medial end of the clavicle and adjacentstructure, such as sternum, first rib, and costal cartilage;and stage 3 marks the progression of osteosclerosis, hyper-ostosis, and hypertrophy of these and other surroundingstructures (2,27). Adjacent joints may develop arthritis orankylosis. In contrast to adults, only the clavicle is in-volved in children, whereas the sternoclavicular joint,sternum, and ribs are rarely affected. Ossification of thecostoclavicular ligament and first costal cartilage withbony masses extending to the region between clavicle andfirst rib and ankylosis of the sternoclavicular joint hasbeen described in adults, particularly in Japanese patients(36,37), but not in children.

Axial Skeleton

Spinal involvement is usually segmental, most commonlyaffecting a single vertebra, although occasionally up to 4adjacent vertebrae, but an individual patient may have upto 5 such lesions (2,27,38). Manifestations in the axialskeleton can take a variety of forms and can occur invarious combinations. They include osteosclerosis of oneor more vertebral bodies with development of hyperosto-sis; osteolytic lesions with variable degree of vertebral col-lapse; spondylitis with or without discitis, in the latter caseresembling infectious spondylodiscitis; paravertebral ossi-fications; and sacroiliitis (2,27). Paravertebral ossifica-tions in SAPHO syndrome most commonly are nonmar-ginal and asymmetrical syndesmophytes similar to, butnot identical with, the syndesmophytes seen in psoriasis(2,27). Note, however, that others consider them to beenthesophytes rather than true syndesmophytes (17). Inchronic cases, florid hyperostosis may result in massivebony bridging, which can evolve into ankylosis of theadjacent disk spaces and associated kyphosis. Once anky-losis is complete, hyperostosis has been observed to re-solve (17). The sacroiliitis of SAPHO syndrome is morefrequently unilateral than seen in ankylosing spondylitisand is characterized by sclerosis and hyperostosis primar-ily on the iliac side of the joint.

Appendicular Skeleton

The long bones are infrequently involved in adult pa-tients, but represent the most common site of involve-ment in children. In the early stages, they typically show

osteolysis in the metaphysis adjacent to the growth plate

(2,14). The extent of periosteal reaction depends on thesize of the involved bone, generally being more pro-nounced in small-diameter bones (14). The lesions healwith sclerosis and progressive hyperostosis. The disorderoriginally called diffuse sclerosing osteomyelitis of themandible is now recognized to represent a form ofSAPHO syndrome, whether occurring in isolation or inconjunction with bone lesions at other sites. It is seen inup to 10% of patients, usually affects the corpus andramus, while the temporomandibular joint is oftenspared, and is frequently accompanied by painful swellingof the overlying soft tissue (2,27,39). Mandibular lesionsare characterized by diffuse unilateral sclerosis, often as-sociated with pronounced periosteal reaction.

Other Imaging Modalities

Whole-body scintigraphy is useful because it not onlyshows increased tracer uptake in the affected bone butfrequently reveals clinically silent lesions. High tracer up-take in the sternocostoclavicular region yields the so-called “bull’s head sign,” with the manubrium sternirepresenting the upper skull and the inflamed sternocla-vicular joint with the adjacent claviculae forming thehorns (40). This configuration is virtually pathognomonicfor SAPHO syndrome, but is not entirely sensitive, althoughit may even be present in SAPHO patients who do not reportsymptoms of the anterior chest wall (41).

Whole-body magnetic resonance imaging (MRI) hasthe same sensitivity as whole-body scintigraphy, but theadded advantage of avoiding radiation exposure, whichbecomes particularly important when repeated imaging isnecessary during follow-up. Conventional MRI is notonly considerably more sensitive than radiography, butalso can show marrow edema as well as adjacent soft tissueinflammation. It is particularly helpful in examining ver-tebral bodies and can be used to monitor disease progres-sion because chronic sclerotic bone lesions exhibit lowsignal intensity in both T1- and T2-weighted images,whereas active lesions appear hypointense on T1- andhyperintense on T2-weighted images. Computed tomog-raphy, especially multi-slice computed tomography withsecondary reconstructions, is best suited for a detaileddepiction of the osteoarticular lesions and is the imagingmodality of choice for the sternoclavicular region, whichis difficult to visualize by conventional radiographs due tothe superimposition of ribs, spine, and mediastinum.

HISTOLOGY

The histologic characteristics of the bone lesions changeover the course of the disease. In the early stages, there isacute inflammation with a predominantly neutrophilicinfiltrate, and both bone resorption and prominent peri-osteal bone formation have been described (5,42,43). Inbiopsy specimens from children with CRMO, multinu-cleated giant cells, granulomatous foci, and necrotic bone

fragments have been observed (5,44). Subsequently, the

ciu

258 The SAPHO syndrome

infiltrate consists of scattered lymphocytes, plasma cells,histiocytes, and only a few polymorphonuclear cells(5,42,43). Memory T lymphocytes of the CD8� subsetonstitute the major cell type (45). In the late stages, thenfiltrate is sparse or absent and enlarged sclerotic trabec-lae as well as marrow fibrosis are observed. There are

Table 2 Inclusion and Exclusion Features of the SAPHOSyndrome (3)

Inclusion features Osteo-articular manifestations ofacne conglobata, acnefulminans, or hidradenitissuppurativa

Osteo-articular manifestations ofPPP

Hyperostosis (of the anteriorchest wall, limbs or spine)with or without dermatosis

CRMO involving the axial orperipheral skeleton with orwithout dermatosis

Sometimes reported Possible association withpsoriasis vulgaris

Possible association with aninflammatory enterocolopathy

Features of ankylosingspondylitis

Presence of low-virulencebacterial infections

Exclusion features Septic osteomyelitisInfectious chest wall arthritisInfections PPPPalmo-plantar keratodermiaDISH except for fortuitous

associationOsteoarticular manifestations of

retinoid therapy

The presence of 1 of the 4 inclusion features is sufficient for apatient to be included in the SAPHO syndrome.

Table 3 Proposed Major and Minor Diagnostic Criteria of N

Major Diagnostic Criteria

(1) Radiologically proven osteolytic/-sclerotic bone lesion(2) Multifocal bone lesions(3) PPP or psoriasis(4) Sterile bone biopsy with signs of inflammation and/

or fibrosis, sclerosis

Two major or 1 major and 3 minor criteria must be fulfilled for aAs a reminder, CRMO is a subtype of NBO, requiring either mult

a chronic (�6 mo) relapsing-remitting disease course (8). Multifocaddition, the proposed diagnostic criteria of NBO include only PPother dermatologic manifestations have been described in childrensyndrome include severe acne and hidradenitis suppurativa in adddebate, with the criteria proposed by Benhamou et al. (3) listing tautoimmune disease in the patients themselves or in first- or secon

those for SAPHO syndrome.

increased numbers of osteoblasts and occasionally oste-oclasts as well (5,42,43).

DIAGNOSIS

Because the signs and symptoms of SAPHO syndrome arenonspecific and the osteoarticular manifestations cover abroad spectrum, the diagnosis is one of exclusion. Thereare no validated diagnostic criteria, but many physiciansapply the inclusion and exclusion criteria formulated byBenhamou et al. (3) (Table 2). The presence of only 1 ofthe 4 inclusion criteria is sufficient to arrive at a diagnosisof SAPHO syndrome. Separate diagnostic criteria havebeen proposed for nonbacterial osteitis, which includesCRMO (Table 3) (11). The diagnosis is relativelystraightforward in patients with typical localizations ofpain (eg, the anterior chest wall), the corresponding ra-diographic findings, and characteristic skin lesions. It ismuch more challenging when atypical sites are involvedor skin manifestations are absent, and it becomes impos-sible in patients with single skeletal lesions that lack signsof hyperostosis. A detailed history, inquiring specificallyabout previous cutaneous and skeletal involvement, mayprovide diagnostic clues. Whole-body scintigraphy orMRI may reveal additional clinically silent sites of osteo-articular involvement. The bone lesions of SAPHO maynot be distinguishable from infectious osteomyelitis orbone neoplasms, which must be excluded through a bi-opsy yielding the appropriate histologic findings and neg-ative bacterial cultures. The main differential diagnoses ofSAPHO syndrome include infectious osteomyelitis, os-teosarcoma, Ewing sarcoma, bony metastasis, eosino-philic granuloma, Paget’s disease, infectious spondylodis-citis, sternoclavicular osteoarthritis, condensing osteitis ofthe clavicle, and osteonecrosis of the medial clavicularepiphysis (13,46). In children, juvenile idiopathic arthri-tis constitutes another differential diagnosis. For example,in a French CRMO cohort, initial diagnoses were infec-

8)

Minor Diagnostic Criteria

A) Normal blood count and good general state of healthB) CRP and ESR mildly to moderately elevatedC) Observation time longer than 6 moD) HyperostosisE) Associated with other autoimmune diseases apart

from PPP or psoriasisF) Grade I or II relatives with autoimmune or

autoinflammatory disease, or with NBO

sis of NBO.one lesions or a single lesion associated with PPP or psoriasis and

d chronicity are not required for inclusion in SAPHO syndrome. Insoriasis, even though severe acne, pyoderma gangrenosum, andRMO (5,6). In contrast, the proposed inclusion criteria for SAPHO

o PPP. The status of psoriasis vulgaris in SAPHO is still a matter ofdition only as “sometimes reported.” An association with anotheree relatives features only in the proposed criteria for NBO, but not

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M.T. Nguyen et al. 259

tious osteomyelitis in 6 of 14 patients, bone tumor in 2,and juvenile idiopathic arthritis in 2 (47). Chest pain dueto anterior chest wall involvement may be mistaken for anacute cardiac event (17).

TREATMENT

Nonsteroidal Anti-InflammatoryDrugs (NSAIDs) and Analgesics

Due to the rarity of the SAPHO syndrome, no random-ized controlled clinical trials have been conducted to eval-uate the efficacy of individual therapeutic modalities.Consequently, treatment is not evidence-based, but de-rived from observations in published case reports andsmall case series, along with expert judgment. Therapy isaimed at symptom relief and mainly includes NSAIDsand analgesics as first-line agents. However, at least onehalf of all SAPHO patients do not experience sufficientpain relief and protection from disease exacerbations withsuch conservative therapy (1,17). Because of the similaritybetween the osteitis of SAPHO syndrome and particu-larly of CRMO with infectious osteomyelitis, numerouspatients have been treated with antimicrobial agents, evenif bacterial cultures prepared from their biopsy yieldednegative results. The vast majority of patients did notderive any benefit from such therapy. However, therehave been a few reports of positive responses (eg, in 4/20patients in a large French cohort (16), and 2/9 patients ina group of Italian patients) (17). Propionibacterium acne is

low-virulence pathogen suspected of playing a role inAPHO syndrome (48). In 14 German patients whoseiopsy was positive for P. acne and another 13 patients

who had not undergone a biopsy, a 16-week course ofantimicrobial therapy was associated with a significantdecrease in disease activity of both the osteitis and thedermatologic lesions (49). However, disease activity re-turned to baseline levels within 3 months following dis-continuation of therapy.

Corticosteroids and Disease-ModifyingAnti-Rheumatic Drugs (DMARDs)

In patients refractory to NSAIDs and analgesics, cortico-steroids can be quite effective, particularly when given asintra-articular injections (1,16,25,50). However, somepatients experience only partial or no relief or requiredoses high enough to induce Cushing syndrome (51-53)and relapse after treatment withdrawal has been observed(47). As steroid-sparing agents or in refractory cases, theuse of DMARDs, particularly methotrexate, sulfasalazine,or azathioprine, has been reported to be beneficial in somepatients, although ineffective in others (11,16,54).

Biologicals

Treatment with biologicals that antagonize tumor necro-sis factor (TNF) has shown promising results in cases of

SAPHO syndrome refractory to NSAIDs, corticoste- e

roids, and DMARDs, including several children (54-61).The most frequently used TNF antagonist is infliximab,but a few patients treated with etanercept or adalimumabhave also been described. The most common dosageschedules are summarized in Table 4, but higher doses—achieved either by increasing the individual dose or byshortening the dosage intervals—have been found neces-sary in some patients. The response is generally rapid,with dramatic improvement even after the first dose, butmore gradual improvement can also occur. Remission ofbone pain has been reported in the majority of patients,but generally requires continued therapy. However, thereare also reports of patients who did not benefit fromTNF� blockade (62). Follow-up has been short in mostases reported to date. Only a limited number of patientsnderwent repeat imaging studies. In some of these, thereas evidence of continued subclinical disease activity withersistence of existing lesions or even development ofew, clinically silent lesions, even though pain had sub-ided completely under TNF blockade (59). The skinesions initially improve, and complete remission of acnend PPP has been described in some patients, but recur-ence, particularly of PPP, was observed in several cases54,63). As has been noted in other indications of TNFlockade, individual patients show differential clinical re-ponses and adverse event profiles to the 3 types of TNFntagonists; therefore, switching of a patient to differentntagonists can be beneficial. Even though there are indi-ations that TNF antagonists are somewhat less effectivehan in other rheumatic diseases, their use should be con-idered in patients whose SAPHO syndrome is refractoryo other therapeutic regimens.

Of note, it has been reported that SAPHO syndromewith PPP and spondylitis) developed during infliximabherapy of a patient with Crohn’s disease (64). Up to 10%f SAPHO patients develop IBD, most frequentlyrohn’s disease and mainly after the onset of SAPHO

ymptoms (8,10-12,16,17,22). Nonetheless, the develop-ent of SAPHO syndrome during infliximab treatment

s unexpected in view of the successful treatment of thisyndrome with infliximab. Note, however, that the para-oxical induction of diseases that are often successfullyreated with TNF blockade is a well-known phenomenon65). In particular, the development of psoriasis has beenbserved in patients with various rheumatic diseases un-ergoing treatment with biologicals and has also beeneported in patients with SAPHO syndrome (54). How-ver, this is the first—and so far only—case of SAPHOyndrome arising during treatment with infliximab (64).

isphosphonates

isphosphonates inhibit bone resorption and have somenti-inflammatory properties. Several small case seriesnd case reports indicate that open-label use of intrave-ous bisphosphonates results in marked pain relief and

ven sustained remission in a considerable portion of

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done

260 The SAPHO syndrome

patients refractory to NSAIDs, corticosteroids, andDMARDS (51,62,66-68), including 2 small series of chil-dren (69,70). Many other patients experience at least par-tial improvement, but a number of treatment failures havealso been reported (54,62,67). Pamidronate has been themost frequently used bisphosphonate, but there are casereports of good results with other types of bisphospho-nates (71-74). The dosage schedules for pamidronatehave been highly variable, ranging from a single infusionof 30 mg (43) to infusions on days 1, 7, 14, 28, and 56(68), but single infusions of 60 mg repeated as needed or60 mg on 3 consecutive days with or without re-treatmentare most common (Table 4). The response can be veryrapid, but in most patients several courses of bisphospho-nates are required to achieve a lasting response. Markers ofbone remodeling, in particular increased levels of serumcross laps at the beginning of therapy and a marked de-crease during therapy, may be prognostic of a goodclinical response to pamidronate (67). Interestingly, flaresof cutaneous involvement have also been reported to di-minish or even subside after bisphosphonate therapy (62),but this is not a consistent finding (66). Adverse effects ofintravenous bisphosphonates in patients with SAPHOsyndrome consist mostly of fever and flue-like symptomsparticularly during or after the first infusion, but haveincluded renal dysfunction in other patient groups.Therefore, it is of particular interest that the use of anoral bisphosphonate also demonstrated effectiveness ina patient with SAPHO syndrome (75). Note that re-peated bone scans do not necessarily show decreasedtechnetium uptake (62,68), although such cases havebeen reported (76).

Surgery

Numerous patients with SAPHO syndrome have under-gone surgical procedures such as saucerization, decortica-tion, and partial or complete resection of the affectedbone. Although this was reported to be beneficial inisolated cases (36,48,77,78), it is generally not recom-mended because there is a high recurrence rate(36,48,50,78). Resections may be necessary, however,in cases of severe functional limitations and importantesthetic concerns, as can occur when the mandible isaffected (39).

DISEASE COURSE AND PROGNOSIS

The course of the disease in individual patients is highlyvariable. In a recently described cohort, 13% of patientshad monophasic disease and 35% experienced a relaps-ing-remitting course for up to a few years, but eventuallyreached remission. The disease took a chronic course withexacerbations separated by brief periods of improvementin the remaining 52% of patients (17). Predictors of achronic disease course in this study were female genderand the presence at disease onset of anterior chest wall

involvement, peripheral arthritis, dermatologic lesions,T P L P P IL

M.T. Nguyen et al. 261

and high levels of acute phase reactants. In partial con-trast, 71% of patients in a French cohort experiencedself-limited disease, whereas the disease became chronic inthe remainder (22). Involvement of additional sites dur-ing the course of the disease is a frequent observation(16,17,79).

Note that the intervals between flares are highly vari-able, even in individual patients, and can range from a fewweeks to several months, sometimes even years. In somecases, exacerbations of bone and skin lesions occur almostsynchronously (24,25), whereas no temporal correlationbetween rheumatologic and dermatologic symptoms isseen in others (16,17). The prognosis is generally consid-ered to be relatively good. Disabling complications arerare (16,17), and even patients with chronic disease werefound to experience gradual improvement (79). None-theless, the peripheral arthritis in SAPHO syndrome maybecome erosive in a minority of patients (16,17). Whenthe inflammation spreads from the affected bones andjoints into the adjacent tissue, soft tissue swelling canresult in venous obstruction and thrombosis. Most fre-quently, this manifests as thoracic outlet syndrome, sub-clavian vein obstruction, and superior vena cava syn-drome (16,27,77). Such soft tissue lesions may bemistaken for a mediastinal tumor and result in unneces-sary biopsy or even mutilating surgical procedures unlessthere is awareness that this can represent a manifestationof SAPHO syndrome (77). In addition, approximately8% to 10% of patients have or develop inflammatorybowel disease, with Crohn’s disease being 3 to 4 timesmore frequent than ulcerative colitis (Table 1) (8,10-12,16,17,22).

The disease course in children is similarly characterizedby periods of exacerbations and remissions with an in-creasing number of lesions over time (10), but CRMO isgenerally considered to be a relatively benign and self-limiting disease without major sequelae. Indeed, healingof lesions with sclerosis and normalization of the bonestructure over a period of 0.5 to 5 years after remissionhave been described in children with CRMO (24). None-theless, the disease remained active in �60% of patients 3to 5 years after diagnosis (28,47). Even a median of 13years after diagnosis, one fourth of CRMO patients werefound to experience chronic pain due to active disease(10). Others reported a high frequency of pathologic frac-tures (49%) and vertebral fractures derived from patho-logic fractures (44%) in patients with CRMO (11). Inaddition, CRMO patients may suffer from permanentbone deformities and limb length abnormalities and evengeneralized growth failure (28,80). Educational outcomesand career choices may also be affected by CRMO (28).

PATHOGENESIS

The pathogenesis of SAPHO syndrome remains un-known and the mechanisms linking osteoarticular and

skin lesions are enigmatic. The highly variable response to

each and every treatment modality used to date suggeststhat a multitude of pathways is involved. Several hypoth-eses have been proposed. One is that bone and skin lesionsarise in response to persistent infection with low-virulencepathogens. Among the microorganisms cultured frombone biopsies of some patients with SAPHO syndrome,P. acne has been most frequently identified (48,49,81).Note, however, that in a vast majority of patients, culturesare negative, even when tested with polymerase chain re-action employing universal primers for eubacterial andmycobacterial genes (45,47), and antibiotics are generallyineffective, even if a few cases with a good clinical re-sponse to antimicrobial agents have been described(16,17). It has also been hypothesized that SAPHO syn-drome represents an autoimmune process triggered by abacterial or viral pathogen via molecular mimicry. Noneof these hypotheses explain why skin lesions precede bonelesion in some patients and follow them in others or whyyears or decades can pass between cutaneous and osteoar-ticular manifestations.

There have been several systematic investigations ofautoantibodies in patients with the SAPHO syndrome(17,18,82). The results were always negative for rheuma-toid factor, anti-citrullinated peptide, and extractable nu-clear antigens with 1 exception (18). Antinuclear antibod-ies (ANA) were negative in all patients of 1 cohort (82)and were not detected at presentation, but developed in 2of 71 patients during follow-up (17). In the third inves-tigation, however, ANA at titers of 1/160 were detected in14 of 90 (16%) patients, yet 10 of these patients nevertook medications associated with the induction of ANA(18). ANA at titers �1/80 were found in almost 37% ofthis cohort. Similarly, 33% of patients with nonbacterialosteitis including CRMO were reported to have ANAtiters �1:120 (11). Their specificity could not be deter-mined. Antithyroid globulin and antithyroid peroxidaseswere detected in 2% to 3% of patients in 2 studies(18,82), but these antibodies were present in 23% and21% of the patients in another cohort, and 6 patients hadovert hyperthyroidism (17).

Genetics

Considering that there are far less than 1000 publishedcases of SAPHO syndrome, the number of familial casesthat have been described is quite substantial. Theseconcern monozygotic twins (83-85), sibling pairs(19,50,86,87) and trios (19,88,89), a mother–daughterpair (90), and several other cases in which the relationshipis not specified (17). In several instances, the affected sib-lings shared numerous human leukocyte antigens (HLA)phenotypes (87,88,91). In addition, a family has beendescribed in which the patient and her grandmother hadSAPHO, the mother had recurrent pustulosis, severeacne, and intermittent multifocal bone pain that had notbeen evaluated, and several other family members had

severe acne and various other skin diseases (92). Of note,

odwPDpgdprhanpmedsovIaa

taaaGstc

262 The SAPHO syndrome

neutrophils from both the primary patient and hermother exhibited a defect in the internal oxidative burst ofneutrophils in response to a variety of stimuli (92). This isnoteworthy because neutrophilic pseudoabscesses arecharacteristic of the dermatoses associated with SAPHOsyndrome, and the early infiltrate in bone lesions is alsodominated by neutrophils.

Among 89 cases of nonbacterial osteitis, includingCRMO, 6% of the families contained more than 1 af-fected member, including father and son, father and 2 ofhis daughters, monozygotic twin sisters, and 2 other pairsof sisters (11). In addition, almost 40% of the patients hada family history of autoimmune diseases (11). Similarly,among 45 CRMO patients, 47% of first- or second-de-gree relatives reportedly had 1 or more chronic inflamma-tory disorder(s), including psoriasis, IBD, arthritis, andsevere acne (93). Several other SAPHO cases with a familyhistory of psoriasis (almost always without psoriatic ar-thritis) have been reported (12,17,24,47,69,94,95),whereas a family history of ankylosing spondylitis seemsto be rare (47).

Although the familial clustering of SAPHO cases ap-pears to be more limited than seen in the spondyloar-thropathies, particularly psoriatic arthritis, it nonethelesssuggests a genetic component in the pathogenesis of thesyndrome. Some of the early studies indicated that thefrequency of HLA-B27 was increased in patients withSAPHO syndrome compared to the general population(1,13), although possession of this antigen was nowherenear as frequent as seen in ankylosing spondylitis (where�85% are positive). Recent studies have reported fre-quencies between 4% in Italy and 18% in France (17)(Table 1). Whether this constitutes an excess is difficult todetermine because no phenotype frequencies for the gen-eral population are provided in these studies. Generally,between 2% and 9% of most populations of Europeandescent are HLA-B27 carriers, but the frequency canrange from 0 to �20 worldwide. In an analysis of 25SAPHO and 120 psoriatic arthritis patients, SAPHOshowed no association with HLA-B27, HLA-Cw6, orHLA-DR antigens, whereas HLA-Cw6 was associatedwith psoriasis and psoriatic arthritis and HLA-B27 wasassociated with psoriatic spondylitis (96).

Insights into possible genetic associations may alsocome from 2 mouse models with nonsynonymous ho-mozygous mutations in the PSTPIP2 gene, encoding theproline serine threonine phosphatase interacting protein2, spontaneously developing features of CRMO. In addi-tion, the SAPHO syndrome shares some features withseveral human genetic auto-inflammatory diseases withautosomal-recessive inheritance, including the Majeedsyndrome, PAPA (pyogenic arthritis, pyoderma gangre-nosum, and acne) syndrome, and deficiency of interleu-kin-1-receptor antagonist (80,93). The Majeed syndromeconsists of CRMO, anemia due to congenital erythropoi-esis abnormalities, and transient neutrophilic dermatoses.

It is due to a homozygous mutation of the LPIN2 gene

(encoding lipin 2) (97). The PAPA syndrome is caused bymutations in PSTPIP1. However, an analysis of geneticsusceptibility factors in patients with SAPHO syndromedid not identify an association of SAPHO syndrome withLPIN2 (19). There also was no association with PSTPIP2r with NOD2/CARD15, a gene implicated in Crohn’sisease, which is a complication in up to 10% of patientsith SAPHO. No mutations in either PSTPIP1 orSTPIP2 were detected in 10 patients with CRMO (11).eficiency of interleukin-1 receptor antagonist (IL-1Ra)

roduction due to homozygous mutations in the IL1RNene results in an autosomal-recessive auto-inflammatoryisease characterized by aseptic multifocal osteomyelitis,eriostitis, and pustulosis (98). Affected patients can beescued by administration of anakinra, the recombinantuman IL-1RA. Whether SAPHO syndrome is associ-ted with genetic variants of IL-1RA or related genes hasot been investigated to date. However, when 6 SAPHOatients whose disease was refractory to a variety of treat-ent modalities were treated with anakinra, 5 of them

xperienced considerable pain relief and a reduction inisease activity, but a complete lack of efficacy was ob-erved in the sixth patient (99). Treatment with anakinraf a child with CRMO who exhibited significantly ele-ated levels of plasma IL-1RA (implying activation of theL-1 pathway) initially resulted in symptom resolutionnd improvement of disease activity, but efficacy was lostfter a year (61).

The only significant genetic association reported forhe SAPHO syndrome to date is with the T309G allelend the GG genotype of the Mdm2-gene, which were notssociated with psoriasis and psoriatic arthritis (100). Anssociation with the p53 single nucleotide polymorphism72C just failed to reach statistical significance in that

tudy. The tumor suppressor protein p53 plays an impor-ant role in cell cycle regulation and apoptosis of damagedells and also regulates the transcription factor NF-�B,

which is central to a variety of proinflammatory pathways.Mdm2, in turn, is the most important negative regulatorof p53. Both of the alleles with increased frequencies inpatients with SAPHO syndrome have been associatedwith ineffective p53 responses, but it remains to be eluci-dated which p53 functions are involved in the develop-ment of this syndrome. Intense expression of TNF�mRNA and protein has been reported in bone biopsyspecimens of a few patients with SAPHO syndrome (52).In addition, activation of the IL-1 pathway as evidencedby elevated levels of plasma IL-1RA was reported in an-other patient (61). The clinical response of SAPHO pa-tients to treatment with TNF or IL-1 blockade (anakinra)further suggests that these inflammatory cytokines play animportant role in the pathogenesis of the SAPHO syn-drome. Therefore, the inhibitory effects of p53/Mdm2axis on NF-�B-induced proinflammatory pathways maybe particularly relevant.

SAPHO syndrome shares a variety of features with the

seronegative spondyloarthropathies (SpAs), including

M.T. Nguyen et al. 263

sacroiliitis, enthesitis, paravertebral ossifications, and an-kylosis. The association with IBD and psoriasis is anothercharacteristic common to both SAPHO syndrome andSpAs. In addition, pustular psoriasis and PPP are difficultto distinguish histologically and clinically and may repre-sent the same entity. On the other hand, carriage of HLA-B27 is classically linked with the SpAs, particularly withankylosing spondylitis, where the prevalence of this anti-gen exceeds 85% (101,102). Nevertheless, HLA-B27 is atbest only moderately overrepresented in patients with SA-PHO syndrome. A better comprehension of the nosologicrelation between SAPHO syndrome and the seronegativeSpAs may eventually provide insights into the pathogen-esis of SAPHO syndrome. Currently, however, such anunderstanding not only remains elusive but also wouldnot be very useful because the pathogenetic mechanismsof the SpAs also remain largely unknown. A variety ofmechanisms have been proposed for ankylosing spondy-litis, but essentially all of them involve HLA-B27 (103).Reactive arthritis is caused by infectious organisms, thepresence of which would exclude a diagnosis of SAPHOsyndrome. It, too, is strongly associated with HLA-B27.

SAPHO syndrome encompasses a broad spectrum ofhyperostotic and osteitic lesions associated with dermato-logic manifestations. It is believed to share some charac-teristics with spondyloarthropathies and other autoim-mune diseases (104), but more likely is in the auto-inflammatory part of the spectrum of immunologicdiseases (105). Recognition of SAPHO syndrome is im-portant to avoid unnecessary invasive procedures and pro-longed antibiotic treatment of osteoarticular lesions.However, the course of the disease is benign and the long-term functional prognosis is good if promptly diagnosedand treated (106).

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