Scholarly article on topic 'The SAPHO Syndrome'

The SAPHO Syndrome Academic research paper on "Clinical medicine"

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Seminars in Arthritis and Rheumatism
OECD Field of science
{synovitis / acne / pustulosis / hyperostosis / osteitis}

Abstract of research paper on Clinical medicine, author of scientific article — Minhchau Thi Nguyen, Andrea Borchers, Carlo Selmi, Stanley M. Naguwa, Gurtej Cheema, et al.

Objective To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, and genetics 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 multifocal osteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles from the retrieved references. Results The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticular disorders that are frequently accompanied by dermatoses characterized by neutrophilic pseudoabscesses, but can also occur in isolation. SAPHO syndrome is rare, although probably underrecognized because its diagnosis may be challenging because of the wide variability in its musculoskeletal and cutaneous manifestations. This is especially true when atypical sites are involved and when specific skin lesions are absent. There are no standardized treatment protocols available. Current treatments are empirical and have the objective of providing relief from the at times debilitating pain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs and analgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have all been beneficial in some patients, but ineffective in others. This suggests that the pathogenesis of SAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteria and immunological dysfunction are hypothesized to play a role. Conclusions The early recognition, diagnosis, and prompt treatment of SAPHO syndrome can prevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly alleviating pain in a majority of affected patients.

Academic research paper on topic "The SAPHO Syndrome"


The SAPHO Syndrome

Minhchau Thi Nguyen, MD,* Andrea Borchers, PhD,* Carlo Selmi, MD,*,f Stanley M. Naguwa, MD,* Gurtej Cheema, MD,* and M. Eric Gershwin, MD*

Objective: To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, and genetics 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 multifocal osteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles from the retrieved references.

Results: The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticular disorders 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 musculoskeletal and cutaneous manifestations. This is especially true when atypical sites are involved and when specific skin lesions are absent. There are no standardized treatment protocols available. Current treatments are empirical and have the objective of providing relief from the at times debilitating pain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs and analgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have all been beneficial in some patients, but ineffective in others. This suggests that the pathogenesis of SAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteria and immunological dysfunction are hypothesized to play a role.

Conclusions: The early recognition, diagnosis, and prompt treatment of SAPHO syndrome can prevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly alleviating 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

Starting in the 1960s, there have been reports of an association between cutaneous manifestations, in particular palmoplantar pustulosis (PPP), pustular psoriasis, hidradenitis suppurativa, and severe acne (ful-minans or conglobata), with certain osteoarticular manifestations like peripheral synovitis or aseptic osteitis affecting the anterior chest wall and other skeletal sites. Since then, more than 50 designations have been used to

*Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis.

"¡"Clinical Immunology, IRCCS Istituto Clinico Humanitas, Milan, Italy.

Address reprint requests to M. Eric Gershwin, MD, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616. E-mail: megershwin@

describe these combinations, the more common ones being pustulotic arthro-osteitis, sternocostoclavicular hyperostosis, acne-associated spondyloarthropathy, acquired hyperostosis syndrome, or chronic recurrent mul-tifocal osteomyelitis. A group of French researchers, suspecting that these disorders might share common characteristics, conducted a national investigation of such cases (1). Their results indicated that a specific type of bone involvement, namely inflammatory osteitis with hyperostosis, constituted a common denominator and exhibited the same characteristics whether accompanied by dermatologic manifestations or not. These bone lesions are mainly localized in the anterior chest wall, but may involve any skeletal segment (2). As a unifying concept, the French researchers proposed to group these disorders under the acronym SAPHO (originally Syndrome Acne

254 0049-0172/12/$-see front matter © 2012 Elsevier Inc. All rights reserved.

Pustulosis Hyperostosis Osteitis, the "S" being changed to Synovitis the following year) (1,3). Even though pustular dermatoses originally appeared to be the unifying element, their presence is not absolutely required because (1) the typical osteoarticular manifestations are identical in the absence or presence ofcutaneous involvement and (2) it has since become more fully appreciated that dermato-logic manifestations can occur years before bone lesions and may have been forgotten, but can also develop long after the osteoarticular lesions.

Note that the original description of the SAPHO syndrome and the inclusion criteria proposed for this entity specifically include cases of chronic recurrent multifocal osteomyelitis (CRMO) (1,3). This condition was first described by Giedion et al. in 1972 (4) under the name of subacute and chronic symmetrical osteomyelitis, and most frequently affects children, but has been reported in adults (5-8), whereas typical manifestations of SAPHO syndrome have been described in children (9). There still is 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 the SAPHO syndrome, including osteitis; hyperostosis; and the association with skin disorders such as PPP, severe acne, pyoderma gangrenosum, and, in rare cases, Sweet syndrome—although in a lower proportion of cases (~30% compared to 50% to 85% in adults). In addition, CRMO-like SAPHO syndrome is associated with inflammatory bowel disease (IBD) (10-13). However, CRMO most frequently affects the metaphyses of tubular bones, whereas other forms of SAPHO syndrome most often involve the axial skeleton, particularly the anterior chest wall. CRMO can affect the sternocostoclavicular region, but this generally manifests as hyperostosis of the medial end of the clavicle and, unlike in adults, spares other elements of this region, including the sternoclavicular joint (14). Nonetheless, in the following, CRMO is considered a subtype of the SAPHO syndrome that affects children much more frequently than adults.

SAPHO syndrome is generally considered to be a rare condition, possibly due to being underdiagnosed. A prevalence estimate of <1/10,000 is frequently mentioned, although it is unclear what this is derived from because there are no actual data. Based on long years ofexperience with SAPHO, a German rheumatologist and SAPHO expert estimates its prevalence to lie somewhere between that ofsystemic lupus erythematosus and scleroderma and provides a figure of 0.04% (ie, 40/100,000) (15). In the original collection of French SAPHO cases overall, the gender distribution was approximately equal (1). Since then, the majority of cohorts comprising more than 20 patients were characterized by a female preponderance, including various patient groups from France, Italy, and Japan (16-20), as had already been noted in an earlier description of pustulotic arthro-osteitis (21). An exception 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 in children and young to middle-aged adults (16,17).


The osteoarticular involvement is generally insidious in onset, but eventually patients will present with pain that is frequently dramatic and incapacitating and may be exacerbated by movement or application of pressure. Soft tissue swelling, often with redness and heat, and limitation of motion at the affected skeletal site(s) are other presenting signs. Morning stiffness is quite frequently reported ranging in severity from mild to lasting several hours, and in cases of long bone involvement, a limp may be evident. Of note, quite a few cases of CRMO were preceded by trauma (23-26). Systemic manifestations are uncommon; however, fever is sometimes reported and modest elevations of erythrocyte sedimentation rate or C reactive protein are common.

In adults, the most commonly affected skeletal site is the anterior chest wall (65% to 90%, Table 1), followed by the spine (in ~30%), with the thoracic spine being most frequently affected, followed by the lumbar and then the cervical spine (2,27). Sacroiliitis is seen in up to 13% to 52% of patients with SAPHO syndrome (2,27). The appendicular skeleton is not a frequent localization in adults with SAPHO syndrome, with 5% to 10% of them showing involvement of the long bones, and 1% to 10% of patients experiencing mandibular lesions. In contrast, long bones represent the most frequent site of involvement in children, where the distal and proximal tibia are most commonly affected, followed by the proximal and distal femur (10,14,23,28). Lesions ofspine, clavicle, pelvis, and other sites are reported with highly variable frequencies. In both adults and children, there can be arthritis of the articulations adjacent to bone lesions, ie, the anterior chest wall and sacroiliac joints in adults, the ankles and knees in children (10,23,28). Synovitis in peripheral joints distant from the sites of bone involvement is seen in ~30% of adults, but more rarely in children (10).

Skin manifestations may be evident at the time of presentation with osteoarticular symptoms, but may have occurred years earlier or may develop later. In an early description of 53 cases, skin involvement occurred within an interval of 2 years before or after the onset of rheuma-tological symptoms in 70% of cases (21), but delays of up to nearly 4 decades have been reported (16,21,29). In the largest cohorts described to date, skin involvement preceded musculoskeletal symptoms in 40% to 68% of patients, occurred simultaneously in <30% of patients, and manifested later in 32% to 60% of cases (16,17,22). At least 15% of adults and more than 70% of children may never experience skin lesions, whereas others may exhibit 2 or even 3 different ones. The cutaneous lesions are neu-trophilic dermatoses. The most common one is PPP, representing 50% to 75% of all dermatologic manifestations (Table 1) and affecting close to 60% of patients with

Table 1 Frequency of Clinical Manifestations in SAPHO Patients

Reference (18) (24) (19)

Country France France Italy

n 120 52 71

Age at diagnosis (mean, range) 37.7 (5-67) 42 (15-73) 45.5 (35.7-54.0)a

Male/female 50/70 26/26 23/48

Years of study 1974-1997 1984-2007 1990-2008

Follow-up (yr) Mean 4.9 (range NA 0

Anterior chest wall involvement (%) 63 73 70

Inflammatory back pain (%) NA 13 24

Spinal (%) 33 34

Sacroiliitis (%) 40 27

Long bones/peripheral (%) 5.8

Mandible (%) 10.8

Peripheral arthritis (%) 33 33

Cutaneous manifestations (N/%) 110 (84) 63 40 (56)

Of those (in %)

PPP overall >58b 52 65

Severe acne overall 29.7 39 25

Psoriasis vulgaris overall c 33 7.5

PPP, isolated 37.6 50

PPP + psoriasis vulgaris 20.8 0

PPP + severe acne 7.9c 12

PPP + hidradenitis suppurativa 2

Psoriasis vulgaris, isolated 11.9 8

Severe acne, isolated 21.8 23

Severe acne + hidradenitis 5


Other manifestations

Inflammatory bowel disease (n/%) 9 (7.5) 2 (4) 2(3)

Of those Crohn's disease 6/9 (67%) 2/2 (100%) 2/2 (100%)

Of those ulcerative colitis 3/9 (33%) 0 0

HLA-B27 (%) 13 18 4

NA, not available; PPP, palmoplantar pustulosis.

aMedian and interquartile range.

bCannot be determined exactly from the data provided because some patients with SA had both PPP and PV, and only data for SA plus PPP

and/or PV were reported.

cThis figure is for the combination of severe acne with PPP and/or psoriasis vulgaris.

extended follow-up (16,17). Of note, many pathologists feel that PPP cannot be distinguished unequivocally from pustular psoriasis, and it has become customary to subsume both entities under pustulosis or PPP. There is still some debate over whether psoriasis vulgaris should be included among the dermatologic manifestations of SAPHO. Although it may represent up to one third of all skin involvement, it is frequently seen in combination with PPP or severe acne and occurs in isolation in only 5% to 10% of cases. Severe acne, ie, acne conglobata and fulminans, affects approximately one fourth of patients with 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 to represent a distinct entity that resembles acne by others. It mainly affects women, yet men predominate among the cases of SAPHO syndrome that have been reported in association with hidradenitis suppurativa (30-32). African Americans appear to be particularly susceptible.

Other rare cutaneous manifestations of the SAPHO syndrome include pyoderma gangrenosum and Sweet's syndrome (17,33-35). Skin involvement is not as frequent in children compared to adults.

RADIOLOGY Radiography

Two of the osteoarticular manifestations of SAPHO syndrome are hyperostosis and osteitis, which are chronic inflammatory reactions involving the cortical and medullary bone. In the initial stages of the disease, radiographs of affected areas are often normal. Early lesions are often purely osteolytic with or without a sclerotic margin, typically accompanied by an endosteal or periosteal reaction (14). With disease progression, these lesions become mixed lytic/sclerotic or entirely sclerotic (14). Chronic lesions are predominantly sclerotic, with cortical thicken-

ing accompanied by narrowing of the medullary canal and enlargement of trabeculae.

Anterior Chest Wall

Anterior chest wall lesions can involve any component of the sternocostoclavicular region. Lesions usually develop in 3 stages: stage 1 is localized to the area of the costoclavicular ligament and may manifest as a primary en-thesopathy; in stage 2, an arthropathy of the sternoclavicular joint develops with osteolytic and osteosclerotic changes of the medial end of the clavicle and adjacent structure, such as sternum, first rib, and costal cartilage; and stage 3 marks the progression of osteosclerosis, hyper-ostosis, and hypertrophy of these and other surrounding structures (2,27). Adjacent joints may develop arthritis or ankylosis. In contrast to adults, only the clavicle is involved in children, whereas the sternoclavicular joint, sternum, and ribs are rarely affected. Ossification of the costoclavicular ligament and first costal cartilage with bony masses extending to the region between clavicle and first rib and ankylosis of the sternoclavicular joint has been described in adults, particularly in Japanese patients (36,37), but not in children.

Axial Skeleton

Spinal involvement is usually segmental, most commonly affecting a single vertebra, although occasionally up to 4 adjacent vertebrae, but an individual patient may have up to 5 such lesions (2,27,38). Manifestations in the axial skeleton can take a variety of forms and can occur in various combinations. They include osteosclerosis of one or more vertebral bodies with development of hyperostosis; osteolytic lesions with variable degree of vertebral collapse; spondylitis with or without discitis, in the latter case resembling infectious spondylodiscitis; paravertebral ossifications; and sacroiliitis (2,27). Paravertebral ossifications in SAPHO syndrome most commonly are nonmar-ginal and asymmetrical syndesmophytes similar to, but not identical with, the syndesmophytes seen in psoriasis (2,27). Note, however, that others consider them to be enthesophytes rather than true syndesmophytes (17). In chronic cases, florid hyperostosis may result in massive bony bridging, which can evolve into ankylosis of the adjacent disk spaces and associated kyphosis. Once anky-losis is complete, hyperostosis has been observed to resolve (17). The sacroiliitis of SAPHO syndrome is more frequently unilateral than seen in ankylosing spondylitis and is characterized by sclerosis and hyperostosis primarily on the iliac side of the joint.

Appendicular Skeleton

The long bones are infrequently involved in adult patients, but represent the most common site of involvement 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 the size of the involved bone, generally being more pronounced in small-diameter bones (14). The lesions heal with sclerosis and progressive hyperostosis. The disorder originally called diffuse sclerosing osteomyelitis of the mandible is now recognized to represent a form of SAPHO syndrome, whether occurring in isolation or in conjunction with bone lesions at other sites. It is seen in up to 10% of patients, usually affects the corpus and ramus, while the temporomandibular joint is often spared, and is frequently accompanied by painful swelling of the overlying soft tissue (2,27,39). Mandibular lesions are characterized by diffuse unilateral sclerosis, often associated with pronounced periosteal reaction.

Other Imaging Modalities

Whole-body scintigraphy is useful because it not only shows increased tracer uptake in the affected bone but frequently reveals clinically silent lesions. High tracer uptake in the sternocostoclavicular region yields the so-called "bull's head sign," with the manubrium sterni representing the upper skull and the inflamed sternocla-vicular joint with the adjacent claviculae forming the horns (40). This configuration is virtually pathognomonic for SAPHO syndrome, but is not entirely sensitive, although it may even be present in SAPHO patients who do not report symptoms of the anterior chest wall (41).

Whole-body magnetic resonance imaging (MRI) has the same sensitivity as whole-body scintigraphy, but the added advantage of avoiding radiation exposure, which becomes particularly important when repeated imaging is necessary during follow-up. Conventional MRI is not only considerably more sensitive than radiography, but also can show marrow edema as well as adjacent soft tissue inflammation. It is particularly helpful in examining vertebral bodies and can be used to monitor disease progression because chronic sclerotic bone lesions exhibit low signal intensity in both T1- and T2-weighted images, whereas active lesions appear hypointense on T1- and hyperintense on T2-weighted images. Computed tomography, especially multi-slice computed tomography with secondary reconstructions, is best suited for a detailed depiction of the osteoarticular lesions and is the imaging modality of choice for the sternoclavicular region, which is difficult to visualize by conventional radiographs due to the superimposition of ribs, spine, and mediastinum.


The histologic characteristics of the bone lesions change over the course of the disease. In the early stages, there is acute inflammation with a predominantly neutrophilic infiltrate, and both bone resorption and prominent peri-osteal bone formation have been described (5,42,43). In biopsy specimens from children with CRMO, multinu-cleated giant cells, granulomatous foci, and necrotic bone fragments have been observed (5,44). Subsequently, the

Table 2 Inclusion and Exclusion Features of the SAPHO Syndrome (3)

Inclusion features Osteo-articular manifestations of acne conglobata, acne fulminans, or hidradenitis suppurativa Osteo-articular manifestations of PPP

Hyperostosis (of the anterior chest wall, limbs or spine) with or without dermatosis CRMO involving the axial or peripheral skeleton with or without dermatosis Sometimes reported Possible association with psoriasis vulgaris Possible association with an

inflammatory enterocolopathy Features of ankylosing

spondylitis Presence of low-virulence bacterial infections Exclusion features Septic osteomyelitis

Infectious chest wall arthritis Infections PPP

Palmo-plantar keratodermia DISH except for fortuitous

association Osteoarticular manifestations of retinoid therapy

The presence of 1 of the 4 inclusion features is sufficient for a patient to be included in 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+ subset constitute the major cell type (45). In the late stages, the infiltrate is sparse or absent and enlarged sclerotic trabec-ulae as well as marrow fibrosis are observed. There are

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


Because the signs and symptoms ofSAPHO syndrome are nonspecific and the osteoarticular manifestations cover a broad spectrum, the diagnosis is one of exclusion. There are no validated diagnostic criteria, but many physicians apply the inclusion and exclusion criteria formulated by Benhamou et al. (3) (Table 2). The presence of only 1 of the 4 inclusion criteria is sufficient to arrive at a diagnosis of SAPHO syndrome. Separate diagnostic criteria have been proposed for nonbacterial osteitis, which includes CRMO (Table 3) (11). The diagnosis is relatively straightforward in patients with typical localizations of pain (eg, the anterior chest wall), the corresponding radiographic findings, and characteristic skin lesions. It is much more challenging when atypical sites are involved or skin manifestations are absent, and it becomes impossible in patients with single skeletal lesions that lack signs of hyperostosis. A detailed history, inquiring specifically about previous cutaneous and skeletal involvement, may provide diagnostic clues. Whole-body scintigraphy or MRI may reveal additional clinically silent sites ofosteo-articular involvement. The bone lesions of SAPHO may not be distinguishable from infectious osteomyelitis or bone neoplasms, which must be excluded through a biopsy yielding the appropriate histologic findings and negative bacterial cultures. The main differential diagnoses of SAPHO syndrome include infectious osteomyelitis, os-teosarcoma, Ewing sarcoma, bony metastasis, eosino-philic granuloma, Paget's disease, infectious spondylodis-citis, sternoclavicular osteoarthritis, condensing osteitis of the clavicle, and osteonecrosis of the medial clavicular epiphysis (13,46). In children, juvenile idiopathic arthritis constitutes another differential diagnosis. For example, in a French CRMO cohort, initial diagnoses were infec-

Table 3 Proposed Major and Minor Diagnostic Criteria of NBO (8)

Major Diagnostic Criteria Minor 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 (A) Normal blood count and good general state of health (B) CRP and ESR mildly to moderately elevated (C) Observation time longer than 6 mo (D) Hyperostosis (E) Associated with other autoimmune diseases apart from PPP or psoriasis (F) Grade I or II relatives with autoimmune or autoinflammatory disease, or with NBO

Two major or 1 major and 3 minor criteria must be fulfilled for a diagnosis of NBO. As a reminder, CRMO is a subtype of NBO, requiring either multifocal bone lesions or a single lesion associated with PPP or psoriasis and a chronic (>6 mo) relapsing-remitting disease course (8). Multifocality and chronicity are not required for inclusion in SAPHO syndrome. In addition, the proposed diagnostic criteria of NBO include only PPP or psoriasis, even though severe acne, pyoderma gangrenosum, and other dermatologic manifestations have been described in children with CRMO (5,6). In contrast, the proposed inclusion criteria for SAPHO syndrome include severe acne and hidradenitis suppurativa in addition to PPP. The status of psoriasis vulgaris in SAPHO is still a matter of debate, with the criteria proposed by Benhamou et al. (3) listing this condition only as "sometimes reported." An association with another autoimmune disease in the patients themselves or in first- or second-degree relatives features only in the proposed criteria for NBO, but not those for SAPHO syndrome.

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


Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Analgesics

Due to the rarity of the SAPHO syndrome, no randomized controlled clinical trials have been conducted to evaluate the efficacy of individual therapeutic modalities. Consequently, treatment is not evidence-based, but derived from observations in published case reports and small case series, along with expert judgment. Therapy is aimed at symptom relief and mainly includes NSAIDs and analgesics as first-line agents. However, at least one half of all SAPHO patients do not experience sufficient pain reliefand protection from disease exacerbations with such conservative therapy (1,17). Because of the similarity between the osteitis of SAPHO syndrome and particularly of CRMO with infectious osteomyelitis, numerous patients have been treated with antimicrobial agents, even if bacterial cultures prepared from their biopsy yielded negative results. The vast majority of patients did not derive any benefit from such therapy. However, there have been a few reports of positive responses (eg, in 4/20 patients in a large French cohort (16), and 2/9 patients in a group of Italian patients) (17). Propionibacterium acne is a low-virulence pathogen suspected of playing a role in SAPHO syndrome (48). In 14 German patients whose biopsy was positive for P. acne and another 13 patients who had not undergone a biopsy, a 16-week course of antimicrobial therapy was associated with a significant decrease in disease activity of both the osteitis and the dermatologic lesions (49). However, disease activity returned to baseline levels within 3 months following discontinuation of therapy.

Corticosteroids and Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

In patients refractory to NSAIDs and analgesics, cortico-steroids can be quite effective, particularly when given as intra-articular injections (1,16,25,50). However, some patients experience only partial or no relief or require doses 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, the use of DMARDs, particularly methotrexate, sulfasalazine, or azathioprine, has been reported to be beneficial in some patients, although ineffective in others (11,16,54).


Treatment with biologicals that antagonize tumor necrosis factor (TNF) has shown promising results in cases of SAPHO syndrome refractory to NSAIDs, corticoste-

roids, and DMARDs, including several children (54-61). The most frequently used TNF antagonist is infliximab, but a few patients treated with etanercept or adalimumab have also been described. The most common dosage schedules are summarized in Table 4, but higher doses— achieved either by increasing the individual dose or by shortening the dosage intervals—have been found necessary in some patients. The response is generally rapid, with dramatic improvement even after the first dose, but more gradual improvement can also occur. Remission of bone pain has been reported in the majority of patients, but generally requires continued therapy. However, there are also reports of patients who did not benefit from TNFa blockade (62). Follow-up has been short in most cases reported to date. Only a limited number of patients underwent repeat imaging studies. In some ofthese, there was evidence of continued subclinical disease activity with persistence of existing lesions or even development of new, clinically silent lesions, even though pain had subsided completely under TNF blockade (59). The skin lesions initially improve, and complete remission of acne and PPP has been described in some patients, but recurrence, particularly of PPP, was observed in several cases (54,63). As has been noted in other indications of TNF blockade, individual patients show differential clinical responses and adverse event profiles to the 3 types of TNF antagonists; therefore, switching of a patient to different antagonists can be beneficial. Even though there are indications that TNF antagonists are somewhat less effective than in other rheumatic diseases, their use should be considered in patients whose SAPHO syndrome is refractory to other therapeutic regimens.

Of note, it has been reported that SAPHO syndrome (with PPP and spondylitis) developed during infliximab therapy of a patient with Crohn's disease (64). Up to 10% of SAPHO patients develop IBD, most frequently Crohn's disease and mainly after the onset of SAPHO symptoms (8,10-12,16,17,22). Nonetheless, the development of SAPHO syndrome during infliximab treatment is unexpected in view of the successful treatment of this syndrome with infliximab. Note, however, that the paradoxical induction of diseases that are often successfully treated with TNF blockade is a well-known phenomenon (65). In particular, the development of psoriasis has been observed in patients with various rheumatic diseases undergoing treatment with biologicals and has also been reported in patients with SAPHO syndrome (54). However, this is the first—and so far only—case of SAPHO syndrome arising during treatment with infliximab (64).


Bisphosphonates inhibit bone resorption and have some anti-inflammatory properties. Several small case series and case reports indicate that open-label use of intravenous bisphosphonates results in marked pain relief and even sustained remission in a considerable portion of

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patients refractory to NSAIDs, corticosteroids, and DMARDS (51,62,66-68), including 2 small series of children (69,70). Many other patients experience at least partial improvement, but a number oftreatment failures have also been reported (54,62,67). Pamidronate has been the most frequently used bisphosphonate, but there are case reports of good results with other types of bisphospho-nates (71-74). The dosage schedules for pamidronate have been highly variable, ranging from a single infusion of 30 mg (43) to infusions on days 1, 7, 14, 28, and 56 (68), but single infusions of60 mg repeated as needed or 60 mg on 3 consecutive days with or without re-treatment are most common (Table 4). The response can be very rapid, but in most patients several courses ofbisphospho-nates are required to achieve a lasting response. Markers of bone remodeling, in particular increased levels of serum cross laps at the beginning of therapy and a marked decrease during therapy, may be prognostic of a good clinical response to pamidronate (67). Interestingly, flares of cutaneous involvement have also been reported to diminish or even subside after bisphosphonate therapy (62), but this is not a consistent finding (66). Adverse effects of intravenous bisphosphonates in patients with SAPHO syndrome consist mostly of fever and flue-like symptoms particularly during or after the first infusion, but have included renal dysfunction in other patient groups. Therefore, it is of particular interest that the use of an oral bisphosphonate also demonstrated effectiveness in a patient with SAPHO syndrome (75). Note that repeated bone scans do not necessarily show decreased technetium uptake (62,68), although such cases have been reported (76).


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


The course of the disease in individual patients is highly variable. In a recently described cohort, 13% of patients had monophasic disease and 35% experienced a relaps-ing-remitting course for up to a few years, but eventually reached remission. The disease took a chronic course with exacerbations separated by brief periods of improvement in the remaining 52% of patients (17). Predictors of a chronic disease course in this study were female gender and the presence at disease onset of anterior chest wall involvement, peripheral arthritis, dermatologic lesions,

and high levels of acute phase reactants. In partial contrast, 71% of patients in a French cohort experienced self-limited disease, whereas the disease became chronic in the remainder (22). Involvement of additional sites during the course of the disease is a frequent observation


Note that the intervals between flares are highly variable, even in individual patients, and can range from a few weeks to several months, sometimes even years. In some cases, exacerbations ofbone and skin lesions occur almost synchronously (24,25), whereas no temporal correlation between rheumatologic and dermatologic symptoms is seen in others (16,17). The prognosis is generally considered to be relatively good. Disabling complications are rare (16,17), and even patients with chronic disease were found to experience gradual improvement (79). Nonetheless, the peripheral arthritis in SAPHO syndrome may become erosive in a minority of patients (16,17). When the inflammation spreads from the affected bones and joints into the adjacent tissue, soft tissue swelling can result in venous obstruction and thrombosis. Most frequently, this manifests as thoracic outlet syndrome, sub-clavian vein obstruction, and superior vena cava syndrome (16,27,77). Such soft tissue lesions may be mistaken for a mediastinal tumor and result in unnecessary biopsy or even mutilating surgical procedures unless there is awareness that this can represent a manifestation of SAPHO syndrome (77). In addition, approximately 8% to 10% of patients have or develop inflammatory bowel disease, with Crohn's disease being 3 to 4 times more frequent than ulcerative colitis (Table 1) (8,1012,16,17,22).

The disease course in children is similarly characterized by periods of exacerbations and remissions with an increasing number of lesions over time (10), but CRMO is generally considered to be a relatively benign and self-limiting disease without major sequelae. Indeed, healing of lesions with sclerosis and normalization of the bone structure over a period of 0.5 to 5 years after remission have been described in children with CRMO (24). Nonetheless, the disease remained active in ~60% of patients 3 to 5 years after diagnosis (28,47). Even a median of 13 years after diagnosis, one fourth of CRMO patients were found to experience chronic pain due to active disease (10). Others reported a high frequency of pathologic fractures (49%) and vertebral fractures derived from pathologic fractures (44%) in patients with CRMO (11). In addition, CRMO patients may suffer from permanent bone deformities and limb length abnormalities and even generalized growth failure (28,80). Educational outcomes and career choices may also be affected by CRMO (28).


The pathogenesis of SAPHO syndrome remains unknown and the mechanisms linking osteoarticular and skin lesions are enigmatic. The highly variable response to

each and every treatment modality used to date suggests that a multitude of pathways is involved. Several hypotheses have been proposed. One is that bone and skin lesions arise in response to persistent infection with low-virulence pathogens. Among the microorganisms cultured from bone biopsies of some patients with SAPHO syndrome, P. acne has been most frequently identified (48,49,81). Note, however, that in avast majority of patients, cultures are negative, even when tested with polymerase chain reaction employing universal primers for eubacterial and mycobacterial genes (45,47), and antibiotics are generally ineffective, even if a few cases with a good clinical response to antimicrobial agents have been described (16,17). It has also been hypothesized that SAPHO syndrome represents an autoimmune process triggered by a bacterial or viral pathogen via molecular mimicry. None of these hypotheses explain why skin lesions precede bone lesion in some patients and follow them in others or why years or decades can pass between cutaneous and osteoar-ticular manifestations.

There have been several systematic investigations of autoantibodies in patients with the SAPHO syndrome (17,18,82). The results were always negative for rheumatoid factor, anti-citrullinated peptide, and extractable nuclear antigens with 1 exception (18). Antinuclear antibodies (ANA) were negative in all patients of 1 cohort (82) and were not detected at presentation, but developed in 2 of 71 patients during follow-up (17). In the third investigation, however, ANA at titers of 1/160 were detected in 14 of 90 (16%) patients, yet 10 of these patients never took medications associated with the induction of ANA (18). ANA at titers >1/80 were found in almost 37% of this cohort. Similarly, 33% of patients with nonbacterial osteitis including CRMO were reported to have ANA titers >1:120 (11). Their specificity could not be determined. Antithyroid globulin and antithyroid peroxidases were detected in 2% to 3% of patients in 2 studies (18,82), but these antibodies were present in 23% and 21% of the patients in another cohort, and 6 patients had overt hyperthyroidism (17).


Considering that there are far less than 1000 published cases of SAPHO syndrome, the number of familial cases that have been described is quite substantial. These concern monozygotic twins (83-85), sibling pairs (19,50,86,87) and trios (19,88,89), a mother-daughter pair (90), and several other cases in which the relationship is not specified (17). In several instances, the affected siblings shared numerous human leukocyte antigens (HLA) phenotypes (87,88,91). In addition, a family has been described in which the patient and her grandmother had SAPHO, the mother had recurrent pustulosis, severe acne, and intermittent multifocal bone pain that had not been evaluated, and several other family members had severe acne and various other skin diseases (92). Of note,

neutrophils from both the primary patient and her mother exhibited a defect in the internal oxidative burst of neutrophils in response to a variety of stimuli (92). This is noteworthy because neutrophilic pseudoabscesses are characteristic of the dermatoses associated with SAPHO syndrome, and the early infiltrate in bone lesions is also dominated by neutrophils.

Among 89 cases of nonbacterial osteitis, including CRMO, 6% of the families contained more than 1 affected member, including father and son, father and 2 of his daughters, monozygotic twin sisters, and 2 other pairs of sisters (11). In addition, almost 40% of the patients had a family history of autoimmune diseases (11). Similarly, among 45 CRMO patients, 47% of first- or second-degree relatives reportedly had 1 or more chronic inflammatory disorder(s), including psoriasis, IBD, arthritis, and severe acne (93). Several other SAPHO cases with a family history of psoriasis (almost always without psoriatic arthritis) have been reported (12,17,24,47,69,94,95), whereas a family history of ankylosing spondylitis seems to be rare (47).

Although the familial clustering of SAPHO cases appears to be more limited than seen in the spondyloar-thropathies, particularly psoriatic arthritis, it nonetheless suggests a genetic component in the pathogenesis of the syndrome. Some of the early studies indicated that the frequency of HLA-B27 was increased in patients with SAPHO syndrome compared to the general population (1,13), although possession of this antigen was nowhere near as frequent as seen in ankylosing spondylitis (where >85% are positive). Recent studies have reported frequencies between 4% in Italy and 18% in France (17) (Table 1). Whether this constitutes an excess is difficult to determine because no phenotype frequencies for the general population are provided in these studies. Generally, between 2% and 9% of most populations of European descent are HLA-B27 carriers, but the frequency can range from 0 to >20 worldwide. In an analysis of 25 SAPHO and 120 psoriatic arthritis patients, SAPHO showed no association with HLA-B27, HLA-Cw6, or HLA-DR antigens, whereas HLA-Cw6 was associated with psoriasis and psoriatic arthritis and HLA-B27 was associated with psoriatic spondylitis (96).

Insights into possible genetic associations may also come from 2 mouse models with nonsynonymous ho-mozygous mutations in the PSTPIP2 gene, encoding the proline serine threonine phosphatase interacting protein 2, spontaneously developing features of CRMO. In addition, the SAPHO syndrome shares some features with several human genetic auto-inflammatory diseases with autosomal-recessive inheritance, including the Majeed syndrome, PAPA (pyogenic arthritis, pyoderma gangre-nosum, and acne) syndrome, and deficiency of interleu-kin-1-receptor antagonist (80,93). The Majeed syndrome consists 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 by mutations in PSTPIP1. However, an analysis of genetic susceptibility factors in patients with SAPHO syndrome did not identify an association of SAPHO syndrome with LPIN2 (19). There also was no association with PSTPIP2 or with NOD2/CARD15, a gene implicated in Crohn's disease, which is a complication in up to 10% of patients with SAPHO. No mutations in either PSTPIP1 or PSTPIP2 were detected in 10 patients with CRMO (11). Deficiency of interleukin-1 receptor antagonist (IL-1Ra) production due to homozygous mutations in the IL1RN gene results in an autosomal-recessive auto-inflammatory disease characterized by aseptic multifocal osteomyelitis, periostitis, and pustulosis (98). Affected patients can be rescued by administration of anakinra, the recombinant human IL-1RA. Whether SAPHO syndrome is associated with genetic variants of IL-1RA or related genes has not been investigated to date. However, when 6 SAPHO patients whose disease was refractory to a variety of treatment modalities were treated with anakinra, 5 of them experienced considerable pain relief and a reduction in disease activity, but a complete lack of efficacy was observed in the sixth patient (99). Treatment with anakinra of a child with CRMO who exhibited significantly elevated levels of plasma IL-1RA (implying activation of the IL-1 pathway) initially resulted in symptom resolution and improvement of disease activity, but efficacy was lost after a year (61).

The only significant genetic association reported for the SAPHO syndrome to date is with the T309G allele and the GG genotype of the Mdm2-gene, which were not associated with psoriasis and psoriatic arthritis (100). An association with the p53 single nucleotide polymorphism G72C just failed to reach statistical significance in that study. The tumor suppressor protein p53 plays an important role in cell cycle regulation and apoptosis ofdamaged cells and also regulates the transcription factor NF-kB, which is central to a variety of proinflammatory pathways. Mdm2, in turn, is the most important negative regulator of p53. Both of the alleles with increased frequencies in patients with SAPHO syndrome have been associated with ineffective p53 responses, but it remains to be elucidated which p53 functions are involved in the development of this syndrome. Intense expression of TNFa mRNA and protein has been reported in bone biopsy specimens of a few patients with SAPHO syndrome (52). In addition, activation of the IL-1 pathway as evidenced by elevated levels of plasma IL-1RA was reported in another patient (61). The clinical response of SAPHO patients to treatment with TNF or IL-1 blockade (anakinra) further suggests that these inflammatory cytokines play an important role in the pathogenesis of the SAPHO syndrome. Therefore, the inhibitory effects of p53/Mdm2 axis on NF-kB-induced proinflammatory pathways may be particularly relevant.

SAPHO syndrome shares a variety of features with the seronegative spondyloarthropathies (SpAs), including

sacroiliitis, enthesitis, paravertebral ossifications, and an-kylosis. The association with IBD and psoriasis is another characteristic common to both SAPHO syndrome and SpAs. In addition, pustular psoriasis and PPP are difficult to distinguish histologically and clinically and may represent the same entity. On the other hand, carriage of HLA-B27 is classically linked with the SpAs, particularly with ankylosing spondylitis, where the prevalence of this antigen exceeds 85% (101,102). Nevertheless, HLA-B27 is at best only moderately overrepresented in patients with SAPHO syndrome. A better comprehension of the nosologic relation between SAPHO syndrome and the seronegative SpAs may eventually provide insights into the pathogenesis of SAPHO syndrome. Currently, however, such an understanding not only remains elusive but also would not be very useful because the pathogenetic mechanisms of the SpAs also remain largely unknown. A variety of mechanisms have been proposed for ankylosing spondylitis, but essentially all of them involve HLA-B27 (103). Reactive arthritis is caused by infectious organisms, the presence of which would exclude a diagnosis of SAPHO syndrome. It, too, is strongly associated with HLA-B27.

SAPHO syndrome encompasses a broad spectrum of hyperostotic and osteitic lesions associated with dermato-logic manifestations. It is believed to share some characteristics with spondyloarthropathies and other autoimmune diseases (104), but more likely is in the auto-inflammatory part of the spectrum of immunologic diseases (105). Recognition of SAPHO syndrome is important to avoid unnecessary invasive procedures and prolonged antibiotic treatment of osteoarticular lesions. However, the course of the disease is benign and the long-term functional prognosis is good if promptly diagnosed and treated (106).


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