Synovitis,acne,pustulosis,hyperostosis,and osteitis syndrome: review and update

Abstract

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a spectrum of heterogeneous diseases characterized by osteoarticular and dermatological manifestations. Osteitis and hyperostosis are core clinical manifestations in SAPHO syndrome, typically affecting multiple areas and possibly progressing to irreversible osteoarticular damage. Most patients with SAPHO have cutaneous involvement, mainly manifested as palmoplantar pustulosis and severe acne. Systemic manifestations are uncommon but occasionally reported. Epidemiological studies suggest the annual prevalence of SAPHO syndrome varies from 0.00144 in 100,000 in Japanese individuals to fewer than 1 in 10,000 in White individuals. The precise etiopathogenesis of SAPHO remains unclear, but it is generally considered an autoinflammatory syndrome that may be related to various etiologies, such as immune dysfunction, infection and genetic predisposition. Owing to the relapsing–remitting disease course, the goal of management is to improve clinical symptoms and prevent disease progression. Various treatments, including nonsteroidal anti-inflammatory drugs, conventional disease-modifying antirheumatic drugs, bisphosphonates, biologics, and antibiotics, are promising options for alleviating the disease.

Keywords

diagnosis etiology imaging SAPHO syndrome treatment

Introduction

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, first proposed by Chamot and colleagues¹ in 1987, is a spectrum of heterogeneous diseases characterized by osteoarticular and dermatological manifestations. The cardinal clinical manifestation in SAPHO syndrome is bone hyperostosis caused by sterile osteitis and osteomyelitis, with or without skin involvement.² Other clinical entities, such as sternocostoclavicular hyperostosis (SCCH), chronic recurrent multifocal osteomyelitis (CRMO), chronic nonbacterial osteomyelitis and mandibular sclerosing osteomyelitis, are also considered a part of SAPHO syndrome.^3–5 Skin lesions of SAPHO syndrome showed neutrophilic infiltration,² which indicate potential links with autoimmune conditions, microbiome alterations, and genetic factors, as in other neutrophilic dermatoses.⁶

In this review, we discuss recent advances concerning the epidemiology, etiopathogenesis, clinical manifestations, diagnosis, disease evaluation, and treatment of SAPHO syndrome.

Epidemiology

The precise epidemiological data for SAPHO syndrome remain unknown. The disease is distributed globally, with an estimated annual prevalence of fewer than 1 in 10,000 in White individuals and 0.00144 in 100,000 in the Japanese population.² To date, over 1000 cases of SAPHO syndrome have been reported worldwide,^7,8 although the real prevalence is considered to be underestimated.

Etiopathogenesis

The precise etiopathogenesis of SAPHO remains unclear, but it is generally considered an autoinflammatory syndrome that may be related to various etiologies, such as immune dysfunction,⁹ infection,¹⁰ and genetic susceptibility.¹¹ An autoinflammatory origin was supported by the elevation of a series of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-8, IL-17, and IL-18.^12,13 The IL-23–helper T cell (Th)17 axis was also reported to be involved in SAPHO syndrome.^14,15 Higher levels of receptor activator nuclear factor kappa-Β ligand (RANKL) were also reported in patients with active disease stage.¹⁶ A recent study found a depletion of natural killer (NK) cells and an imbalance of Th17 and regulatory T (Treg) cells in patients with SAPHO, which may be related to immune inflammation.¹⁷ The potential inflammation-mediated pathogenesis was further supported by the response to biologics targeting TNF-α, IL-1 and the IL-17–IL-23 axis.¹⁸ In addition, several studies have isolated Propionibacterium acnes, Staphylococcus aureus, Haemophilus parainfluenzae, and actinomycetes in SAPHO osteitis lesions,¹⁰ among which P. acnes was the most common species.¹⁹ The interaction between transcription factor Forkhead Box O1 (FoxO1), P. acnes, NLRP3-inflammasome, and IL-1β may play a role in the development of osteitis.¹³ The genetic susceptibility of SAPHO syndrome remains to be investigated. Family aggregation of SAPHO syndrome has been reported.^20–24 Certain single nucleotide polymorphisms (MDM2 T309G, p53 G72C, rs6908425 T>C in CDKAL1) were found to be associated with SAPHO syndrome.^25,26 Mutation in the NCSTN subunit of γ-secretase was identified in a patient with sporadic SAPHO with the manifestation of hidradenitis suppurativa.²⁷ Some genes on chromosomes 1 and 18 (LPIN2, PSTPIP2, and NOD2) were also found to be associated with conditions similar to SAPHO syndrome but not in SAPHO syndrome itself.²⁸ The connection between SAPHO syndrome and certain human leukocyte antigens (HLAs; including HLA-A26, HLA-B27, HLA-B39, and HLA-B61) has been controversial.^2,29–33 The potential etiologies of SAPHO syndrome are summarized in Table 1.

Table 1.

Potential etiologies of SAPHO syndrome.

Potential etiologies	Evidence	References
Immune dysfunction	Elevation of a series of proinflammatory cytokines (TNF-α, IL-1, IL-8, IL-17, IL-18)	Hurtado-Nedelec and colleagues¹²; Berthelot and colleagues¹³
	Involvement of the IL-23/Th17 axis	Firinu and colleagues¹⁴; Wendling and colleagues¹⁵
	Elevation of RANKL in the active group of patients	Zhang and colleagues¹⁶
	Depletion of NK cells and an imbalance of Th17/Treg cells	Xu and colleagues¹⁷
	Generally good response to biologics	Daoussis and colleagues¹⁸
Infection	Certain bacterial species (Propionibacterium acnes, Staphylococcus aureus, Haemophilus parainfluenzae, and actinomycetes) were isolated in SAPHO lesions.	Rozin¹⁰; Colina and colleagues¹⁹
Infection	Interaction between FoxO1, P. acnes, NLRP3-inflammasomes and IL-1β	Berthelot and colleagues¹³
Genetic susceptibility	Family aggregation	Gonzalez and colleagues²⁰; Kurc and colleagues²¹; Huaux and colleagues^22,23; Dumolard and colleagues²⁴
	Certain single nucleotide polymorphisms (MDM2 T309G, p53 G72C, rs6908425 T>C in CDKAL1) were found to be associated with SAPHO syndrome.	Assmann and colleagues²⁵; Li and colleagues²⁶
	Mutation in the NCSTN subunit of γ-secretase was identified in a patient with sporadic SAPHO and hidradenitis suppurativa.	Li and colleagues²⁷
	Possible connection with HLA (HLA-39, HLA61)	De Souza and colleagues³¹; Khanna and El-Khoury³²; Thakur and colleagues³³

FoxO1, Forkhead Box O1; HLA, human leukocyte antigen; IL, interleukin; NK, natural killer; RANKL, receptor activator nuclear factor kappa-B ligand; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis; Th, helper T cell; TNF, tumor necrosis factor; Treg, regulatory T cell.

Clinical manifestations

Osteitis and hyperostosis are the core clinical manifestations in SAPHO syndrome, which typically affect multiple areas and may progress into irreversible bone and joint damage.³⁴ The most commonly affected area is the anterior chest wall (ACW), followed by the axial skeleton (including the spine and the sacroiliac joints), the long bones of the extremities, the irregular bones (such as mandible), and the peripheral joints. ACW involvement, which occurs in 65–90% of patients,^35–38 is highly characteristic of SAPHO syndrome. More specifically, the typical affected structures of the ACW include the sternocostal joints, the sternoclavicular joints and the costoclavicular ligament. The surrounding soft tissue can become reddish and swollen, leading to the compression of nearby structures.³⁷ Approximately 32–52% of patients have axial involvement, which manifests as pain in the spine or gluteal region.^36,37 This group of patients usually presents with more serious clinical manifestations and requires more aggressive treatment.⁸ Peripheral bone and joint involvement is common in patients with SAPHO, which occur in 65.8–82.9% of patients.^8,9

Most patients with SAPHO have cutaneous involvement, mainly manifested as palmoplantar pustulosis (PPP) and severe acne (SA), which are shown in Figure 1.³⁴ PPP, which is recognized as a special type of psoriasis, is characterized by chronic, recurrent, sterile, small pustules and vesicles.³⁹ Among the 354 Chinese patients in the cohort, 94.6% reported skin involvement, of whom 91.9% had PPP, 14.3% had SA, and 15.8% had psoriasis vulgaris.⁸ Psoriatic nail disease has also been reported in some patients.⁹ Skin manifestations can occur at any stage of the disease or be absent. A majority of the patients (over 70%) develop both cutaneous and osteoarticular symptoms within 2 years,^8,40,41 although longer intervals have been reported.^40,42

Figure 1.

Characteristic cutaneous manifestations of SAPHO syndrome: (a) palmoplantar pustulosis (PPP); (b) severe acne (SA).

Systemic manifestations such as fever and elevation of inflammatory markers are uncommon but occasionally reported.⁷ Other extra-articular manifestations include inflammatory bowel disease,⁴³ pulmonary involvement,⁴⁴ venous thrombosis (most commonly affecting the subclavian vein),⁴⁵ dura mater hypertrophy,⁴⁶ and uveitis.⁴⁷

Diagnosis

The most widely applied diagnostic criteria were proposed by Benhamou and colleagues⁴⁸ in 1988, who established the diagnosis of SAPHO syndrome on the basis of clinical manifestations and radiological examinations, including bone, articular or skin manifestations. Another commonly used diagnostic criterion was proposed in 1994 and revised in 2003 by Kahn and Kahn,⁴⁹ who established the diagnosis of SAPHO syndrome mainly on the basis of clinical symptoms. The diagnostic criteria are summarized in Table 2.

Table 2.

Diagnostic criteria for SAPHO syndrome.

Benhamou and colleagues⁴⁸	Kahn and Khan⁴⁹	Kahn⁵⁰
At least 1 of the following 4 conditions: (1) Osteoarticular manifestations of acne conglobate, acne fulminans, or hidradenitis suppurativa; (2) Osteoarticular manifestation of PPP; (3) Hyperostosis (of the ACW, limbs or spine) with or without dermatosis; (4) CRMO involving the axial or peripheral skeleton with or without dermatosis	At least 1 of the following 3 conditions: (1) Chronic recurrent multifocal sterile and axial osteomyelitis, with or without dermatosis (2) Acute, subacute, or chronic arthritis associated with PPP, pustular psoriasis, or SA (3) Any sterile osteitis associated with PPP, pustular psoriasis, or SA	At least 1 of the following 5 conditions: (1) Bone–joint involvement associated with PPP and psoriasis vulgaris (2) Bone–joint involvement associated with SA (3) Isolated sterile hyperostosis/osteitis (4) CRMO (children) (5) Bone–joint involvement associated with chronic bowel diseasesExclusion: Infectious osteitis, tumoral conditions of bone, non-inflammatory condensing lesions of bone.

ACW, anterior chest wall; CRMO, chronic recurrent multifocal osteomyelitis; PPP, palmoplantar pustulosis; SA, severe acne; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis.

Currently, no specific clinical features or laboratory findings have been verified to confirm the diagnosis of SAPHO syndrome. Based mostly on clinical and radiological manifestations, the diagnosis of SAPHO syndrome is, to some extent, a diagnosis of exclusion. However, for patients without the typical pattern of skin lesions and osteoarticular involvement (e.g. with long/flat bone involvement), the diagnosis remains challenging.

Differential diagnosis

Considering the complexity of manifestations of SAPHO syndrome, other inflammatory, infectious, and neoplastic etiologies should be considered. For example, Sonozaki syndrome [or pustulotic arthro-osteitis (PAO)], which belongs to the group of psoriatic arthritis, includes PPP as well as arthro-osteitis, which typically involves the sternoclavicular joint.^51,52 Considering the overlaps with other clinical entities, patients with SAPHO syndrome should be distinguished from patients with other osteoarticular diseases, with or without skin manifestations, and other systematic autoinflammatory diseases (Table 3).

Table 3.

Differential diagnosis of SAPHO syndrome.

Symptoms of SAPHO syndrome	Alternative diagnoses
Synovitis	Rheumatoid arthritis, spondyloarthritis
Acne	PAPA syndrome, Behçet's disease
Pustulosis	Pustular psoriasis, psoriasis arthritis, Sneddon–Wilkinson syndrome, Sonozaki syndrome (pustulotic arthro-osteitis)
Hyperostosis	Diffuse idiopathic skeletal hyperostosis
Osteitis	Chronic bacterial osteomyelitis, Ewing sarcoma, osteosarcoma, metastatic tumors, Paget’s disease, deficiency in interleukin-1 receptor antagonist syndrome

PAPA, pyogenic arthritis, pyoderma gangrenosum, and acne; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis.

Disease evaluation

A comprehensive evaluation is important for the diagnosis and management of SAPHO syndrome. As shown in Figure 2 and Table 4, the disease shows unique patterns of vertebral involvement by multiple imaging techniques,⁵³ yet manifestations may vary with the age of onset, the affected regions, and the course of disease. A series of inflammatory markers and bone metabolites have been found to be useful in quantifying the inflammatory status of SAPHO syndrome. In addition, patient-reported outcomes (PROs) have been widely used in the evaluation of a variety of chronic diseases, including SAPHO syndrome, which better reflect the functional impairment of the disease.

Figure 2.

Characteristic radiological manifestations of SAPHO syndrome. CT revealed bone cortical destruction and osteosclerosis of bilateral sternoclavicular joints, and swelling of the surrounding soft tissues (a). Whole spinal CT showed bone destruction in multiple vertebrae (b). MRI demonstrated multiple patchy, short T1 and long T2 (d) signals of lumbar vertebrae. WBBS showed increased radioactivity in the left sternoclavicular joint, the left first anterior rib, the second and fourth lumbar vertebrae, and the right iliac joint (e). PET/CT showed bone destruction and increased glucose metabolism in left clavicle bone (f) and vertebra (g).

Table 4.

Imaging techniques used in SAPHO syndrome.

Imaging techniques	Typical findings	Advantages	Disadvantages	References
X-ray	Irregular bone morphology, cortical thickening, increased density of the medullary cavity	Economic and classical tools to detect osteoarticular changes in the long bones	Low sensitivity in detecting early lesions	Earwaker and Cotten³⁶; Dihlmann and Dihlmann³⁷; Fritz and colleagues⁵⁴
CT	Bone hyperplasia and bone bridge formation at the attachment point of the costoclavicular ligament	High density and spatial resolution; the ability to detect osteoarticular changes at early stages	Low sensitivity in detecting soft tissue; ionizing radiation	Xu and colleagues⁵⁵; Suzuki and colleagues⁵⁶
MRI	Bone marrow edema (low signal on T1WI sequence, a high signal on T2WI and short-TI inversion recovery sequence, and marked enhancement)	Higher specificity in active inflammation in bone and soft tissue	Low sensitivity in detecting structural bone changes	Depasquale and colleagues³⁷
WBBS	‘Bull’s head’ pattern (high uptake of the ‘sternocostoclavicular’ joint and the sternal angle)	Demonstrating multifocal osteoarticular lesions at the same time; facilitating the diagnosis of patients with nonclassical SAPHO	Inability to determine the activity of lesions	Carr⁵⁷; Schaub and colleagues⁵⁸; Duan and colleagues⁵⁹
PET/CT	Multiple skeletal lesions in the ACW or spine with low to moderate ¹⁸F-FDG uptake and concurrent osteolysis and osteosclerosis	Demonstrating the location and distribution of inflammation; facilitating the differential diagnosis from bone metastasis	Uncertain ability to determine disease activity; expensive	Kohlfuerst and colleagues⁶⁰; Sun and colleagues⁶¹; Patel and colleagues⁶²; Takeuchi and colleagues⁶³

ACW, anterior chest wall; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis; WBBS, whole-body bone scintigraphy.

Imaging assessment

X-ray and computed tomography

Conventional X-ray and computed tomography (CT) scans are classical choices to assess bone hypertrophy and osteitis. X-ray imaging can detect osteoarticular changes in the long bones at relatively late stages, with characteristic manifestations including irregular bone morphology, cortical thickening, increased density of the medullary cavity with or without low-density destruction areas.^36,37 However, the low sensitivity of X-ray to detect lesions at early stages, especially those in the ACW, may lead to delayed diagnosis.⁵⁴

The high density and spatial resolution of a CT scan facilitates its use in detecting osteoarticular lesions that are difficult to observe on X-ray. The ability to clearly reveal bone hyperplasia at the attachment point of the costoclavicular ligament at an early stage makes CT an important diagnostic tool for SAPHO syndrome. The whole-spine CT can clearly demonstrate the distinct characteristics of spinal lesions, in which the location of vertebral corner and ‘kissing’ involvement pattern are indicative of SAPHO syndrome.⁵⁵

Magnetic resonance imaging

With an advantage over CT in assessing early and active disease, magnetic resonance imaging (MRI) can be employed as a guide for treatment and follow up. Bone marrow edema shown on MRI suggests an active disease state, presenting as a low signal on T1WI, a high signal on T2WI and short-TI inversion recovery images, and marked enhancement on enhanced scans.³⁷

Whole-body bone scintigraphy

Whole-body bone scintigraphy (WBBS) has the advantages of demonstrating multifocal osteoarticular lesions at the same time and finding clinically insidious lesions.⁵⁷ The typical ‘bull’s head’ pattern on WBBS, that is, the high uptake of the ‘sternocostoclavicular’ joint and the sternal angle is highly specific for SAPHO syndrome.⁵⁸ The bull’s head sign is especially important for the diagnosis of patients with nontypical SAPHO who have atypical cutaneous lesions or lack cutaneous manifestations.⁵⁹ Based on WBBS manifestations, the osteoarticular involvement in SAPHO syndrome can be categorized into three distinct patterns, that is, the spinal type, the costal type and the sternoclavicular type.⁶⁴ However, both active and chronic lesions manifest as high uptake areas on WBBS, which means WBBS cannot determine the disease activity of lesions.

Positron emission tomography/CT

Positron emission tomography (PET)/CT can demonstrate the location and distribution of inflammation in osteoarticular lesions.⁶⁰ The typical PET/CT findings of SAPHO syndrome are multiple skeletal lesions in the ACW or spine with low to moderate ¹⁸F-FDG uptake and concurrent osteolysis and osteosclerosis.⁶¹ In addition, PET/CT serves as an important diagnostic tool to differentiate benign lesions from bone metastasis.^62,63 However, the ability of PET/CT to determine disease activity in SAPHO syndrome requires further investigation.

Laboratory tests

Elevation of nonspecific inflammatory markers [e.g. erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] can be seen in the active phase of the disease.^8,65 During the improvement and relapse periods, serum amyloid A appeared to show higher sensitivity than CRP.⁶⁶ An anomaly of proinflammatory and anti-inflammatory cytokine expression was observed in active SAPHO patients, presenting as higher levels of serum TNF-α, IL-6, IL-8, and IL-17A levels.^12,16 Raised immunoglobulin (Ig)G4 levels are reported in 23% of patients with SAPHO and are associated with higher disease activity.⁶⁷ Abnormal levels of bone metabolites may also occur, manifesting as an increase in the osteoclast marker β-isolated C-terminal peptide (β-CTX) and a decrease in the osteoblast marker osteocalcin.⁶⁸ An increased RANKL level and RANKL/osteoprotegerin (OPG) ratio are seen in patients with active SAPHO.¹⁶ The frequency of HLA-B27 was not significantly higher than that in the normal population.⁹ Potential laboratory markers of SAPHO syndrome are summarized in Table 5.

Table 5.

Potential laboratory markers of SAPHO syndrome.

Potential laboratory markers	Findings	References
ESR	Elevated level of ESR during active stages	Cao and colleagues⁸; Przepiera-Bedzak and colleagues⁶⁵
Serum CRP	Elevated level of serum CRP during active stages	Cao and colleagues⁸; Przepiera-Bedzak and colleagues⁶⁵
Serum amyloid A	Elevated during the acute onset of disease; more sensitive than CRP during improvement and relapse periods	Wekell and colleagues⁶⁶
Serum cytokines	Elevated levels of TNF-α, IL-6, IL-8, IL-17A in patients with active SAPHO	Hurtado-Nedelec and colleagues¹²; Zhang and colleagues¹⁶
Bone metabolites	Elevated level of β-CTX and reduced level of osteocalcin	Chen and colleagues⁶⁸
Bone metabolites	Elevated level of RANKL and RANKL/OPG ratio in active groups of patients with SAPHO	Zhang and colleagues¹⁶

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL, interleukin; OPG, osteoprotegerin; RANKL, receptor activator nuclear factor kappa-Β ligand; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis; TNF, tumor necrosis factor.

Patient-reported outcomes

Studies based on PROs on SAPHO syndrome are limited. A nationwide patient survey in Germany showed a high impact of SAPHO syndrome on patients’ general health and quality of life, mainly due to musculoskeletal symptoms.⁶⁹ Further investigation is needed to explore the usefulness of PROs to reflect the treatment efficacy of drugs and the functional status of patients.

Treatment

Strategy

To date, most studies on the treatment of SAPHO syndrome are case reports, case series, or observational cohorts. Evidence based on randomized clinical trials is still lacking. As a result, no consensus has been reached on the treatment of SAPHO syndrome.

The first and primary goal of treatment is the improvement of clinical symptoms, including ostealgia and skin rash. Second, treatment should take effect in slowing the progression of joint involvement and the regression of articular function, thereby improving patients’ quality of life in the long term. Table 6 summarizes the current treatment options on SAPHO syndrome.

Table 6.

Treatment on SAPHO syndrome.

Categories	Drugs	Research type	Response for osteoarticular symptoms	Response evaluated by radiology	Response for cutaneous symptoms	Decrease in inflammatory markers	References
NSAIDs	Diclofenac	Case report	+	N/A	N/A	N/A	Su and colleagues⁷⁰
Corticosteroids	Oral prednisone	Case report	+	N/A	Remission of PPP and nail lesions	N/A	Wang and colleagues⁷¹
DMARDs	Methotrexate	Case report	Remission in skeletal pain and chest pain	Remission in bone marrow edema and pleural effusions	N/A	+	Vekic and colleagues⁷²; Akcaboy and colleagues⁷³; Hasegawa and colleagues^74; Genovese and colleagues⁷⁵
Antibiotics	Azithromycin and doxycycline	Retrospective study	N/A	N/A	+		Aljuhani and colleagues²⁹
Bisphosphonate	pamidronate	Retrospective and prospective study	+	Decrease the bone marrow edema score of vertebrae MRI	N/A	+	Aljuhani and colleagues²⁹; Delattre and colleagues⁷⁶; Liu and colleagues⁷⁷; Zwaenepoel and Vlam⁷⁸
TNF-α inhibitor	Infliximab	Case report,	+	uncovered new active bone lesions	±	+	De Souza and colleagues³¹; Fruehauf and colleagues⁷⁹
	Adalimumab	Case series	+	–	+	+	Vekic and colleagues⁷²; Genovese and colleagues⁷⁵; Garcovich and colleagues⁸⁰
	Etanercept	Case series and case report	+	N/A	+	+	Aljuhani and colleagues²⁹; Zhang and Gao⁸¹; Vilar-Alejo and colleagues⁸²; Zhang and colleagues⁸³
	Certolizumab pegol	Case report	+	N/A	+	+	Kamata and Minota⁸⁴
IL-17/23 inhibitor	Ustekinumab	Case series	–	N/A	+	N/A	Wendling and colleagues¹⁵
IL-17/23 inhibitor	Secukinumab	Case series	–	N/A	+	N/A	Wendling and colleagues¹⁵
	Secukinumab	Observational study	+	+	+	N/A	Assmann and colleagues⁸⁵
IL-6 inhibitor	Tocilizumab	Case report	+	N/A	– (new-onset cutaneious lesions)	+	Fujita and colleagues⁸⁶
	Tocilizumab	Case series	+ (persisting chronic osteomyelitis)	+	N/A	+	Sato and colleagues⁸⁷
	Tocilizumab	Case series	+ (aggravation of osteoarticular lesions)	N/A	– (new-onset cutaneious lesions)	+	Sun and colleagues⁸⁸
IL-1 inhibitor	Anakinra	Retrospective study	+	N/A	+	+	Wendling and colleagues⁸⁹
JAK inhibitor	Tofacitinib	Case report	+	Improvement in synovial inflammation, synovial hypertrophy, and joint effusion	N/A	+	Yang and colleagues⁹⁰
PDE-4 inhibitor	Apremilast	Case report	+	N/A	+	N/A	Adamo and colleagues⁹¹

+, general improvement without specifying certain symptoms; –, no improvement; ±, contradictory results reported by previous studies.

DMARD, disease-modifying antirheumatic drug; IL, interleukin; MRI, magnetic resonance imaging; N/A, not available/applicable; NSAID, nonsteroidal anti-inflammatory drug; PDE-4, phosphodiesterase type 4; PPP, palmoplantar pustulosis; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis; TNF, tumor necrosis factor.

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally regarded as first-line medications for pain relief and symptom control of SAPHO syndrome. NSAIDs work quickly and remarkably for patients at the diagnostic stage of disease. However, NSAID monotherapy has shown limited effects in patients with extensive osteomyelitis.⁹² The gastrointestinal side effects of NSAIDs should be taken into consideration.

Disease-modifying antirheumatic drugs

Conventional disease-modifying antirheumatic drugs (cDMARDs) are usually recommended as second-line options, and the responses to cDMARDs vary among different patients. For patients with peripheral joint involvement and relatively low levels of axial spine joint involvement, the administration of methotrexate (MTX) could be effective.^72–74 Improvement of peripheral osteoarticular symptoms and pleural effusions could occur within several weeks to months. However, the efficacy of MTX for the treatment of osteitis, osteomyelitis or enthesitis is uncertain. Other cDMARDs, including sulfasalazine, hydroxychloroquine, leflunomide, thalidomide, and colchicine, have been reported to be beneficial in SAPHO syndrome based on case reports or case series.^7,40,93 Further evidence is needed to determine the efficacy of these agents.

Corticosteroids

Systematic or intra-articular corticosteroids work quickly but transiently.⁹⁴ Relapses tend to occur when treating cutaneous lesions and appear to be even more serious than before.⁹⁵ Taking adverse effects into consideration, corticosteroids are preferably used as a bridge treatment in moderate doses and for a short term.

Bisphosphonates

Bisphosphonates consistently inhibit osteoclast activity and exert anti-inflammatory effects.⁹⁶ The use of intravenous bisphosphonates (especially pamidronate) for SAPHO syndrome has been reported, demonstrating partial or full remission of both ostealgia and cutaneous lesions.^29,78

Targeted drugs

Use of anti-TNF-α biologics has been frequently reported. Previous reports of the treatment of SAPHO syndrome with infliximab,⁷⁹ adalimumab,^75,80 and etanercept⁹⁷ have proved the effectiveness of these treatments for osteoarticular and cutaneous lesions. However, during anti-TNF-α therapy, some patients develop new paradoxical skin lesions, which present as psoriasiform scaly plaques or pustular lesions.^98,99

Other less commonly used biologics, such as anakinra,⁸⁹ ustekinumab,¹⁵ secukinumab,^15,85 and apremilast,⁹¹ have also shown beneficial effects in some patients. Although administration of tocilizumab, an anti-IL-6 agent, showed efficacy to some extent, aggravation or development of lesions were quite common. Existing observations indicate that tocilizumab may not be an ideal option for SAPHO syndrome, and it should be considered with caution.^86–88

Tofacitinib, a small-molecule nonspecific JAK 1 and JAK 3 inhibitor, was used to treat a patient refractory to SAPHO and demonstrated amelioration in terms of clinical symptoms, inflammatory parameters, and MRI.⁹⁰

Antibiotics

Since infection by P. acnes is thought to be a possible pathogenetic trigger of SAPHO syndrome, especially for patients with SA,¹³ antibiotics have also been considered for treatment. Tetracyclines,²⁹ clindamycin,¹⁰⁰ and azithromycin²⁹ have been reported to be successful in treating some cases of acne but show little efficacy against other symptoms. Skin involvement in SAPHO syndrome mainly manifests as PPP, in which condition antibiotics show an effect that is curative but not as dramatic as that in the treatment of acne.

Prognosis

SAPHO syndrome is a chronic disease that typically follows a relapsing–remitting disease course.¹⁰¹ Some patients undergo one or two attacks with eventual spontaneous resolution. Others experience a prolonged and sometimes disabling evolution with the appearance of new cutaneous or osteoarticular manifestations. The prognosis of SAPHO syndrome is generally good.^40,102 However, for patients with pathological fractures in the vertebral bodies or clavicle, the prognosis is not optimistic.¹⁰³

Conclusion

SAPHO syndrome is a chronic inflammatory disorder characterized by osteoarticular and dermatological involvement. Osteitis and hyperostosis are considered the core clinical manifestations, which mainly affect the axial skeleton with characteristic involvement of the ACW. A wide spectrum of neutrophilic dermatoses is associated with the disease, with PPP and SA most commonly observed. The pathogenesis remains unclear, yet SAPHO syndrome is considered an autoinflammatory disorder related to a variety of genetic and environmental factors and immune dysregulation. Diagnosis is still challenging due to the clinical heterogeneity of the disease. A comprehensive evaluation including imaging and laboratory examinations is important for early diagnosis and treatment. A variety of therapeutic options, including bisphosphonates and targeted drugs, have been proposed to alleviate symptoms and prevent disease progression.

Footnotes

Acknowledgements

Shuang Liu and Mingwei Tang contributed equally to this manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the CAMS Initiative for Innovative Medicine (grant number 2017-I2M-3-001), the Capital Medical Research and Development Fund (grant number 2016-4-40112), and the National Key Research and Development Program of China (grant number 2016YFC0901500).

Conflict of interest statement

The authors declare that there is no conflict of interest.

Clinical trial registration

Not applicable.

ORCID iD

Chen Li

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