Treatment and monitoring of SAPHO syndrome: a systematic review

Background and objectives Synovitis acne pustulosis hyperostosis osteitis (SAPHO) is a rare heterogeneous disease of unknown aetiopathology. Externally validated and internationally agreed diagnostic criteria or outcomes and, as a result, prospective randomised controlled trials in SAPHO are absent. Consequently, there is no agreed treatment standard. This study aimed to systematically collate and discuss treatment options in SAPHO. Methods Following ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ guidance, a systematic literature search was conducted using PubMed, Scopus and Web of Science databases. Prospective clinical studies and retrospective case collections discussing management and outcomes in SAPHO involving five or more participants were included. Articles not published in English, studies not reporting defined outcomes, and studies solely relying on patient-reported outcomes were excluded. Results A total of 28 studies (20 observational, 8 open-label clinical studies) reporting 796 patients of predominantly European ethnicity were included. Reported therapies varied greatly, with many centres using multiple treatments in parallel. Most patients (37.1%) received non-steroidal anti-inflammatory drugs alone or in combination. Bisphosphonates (22.1%), conventional (21.7%) and biological (11.3%) disease-modifying antirheumatic drugs were the next most frequently reported treatments. Reported outcomes varied and delivered mixed results, which complicates comparisons. Bisphosphonates demonstrated the most consistent improvement of osteoarticular symptoms and were associated with transient influenza-like symptoms. Paradoxical skin reactions were reported in patients treated with TNF inhibitors, but no serious adverse events were recorded. Most treatments had limited or mixed effects on cutaneous involvement. A recent study investigating the Janus kinase inhibitor tofacitinib delivered promising results in relation to skin and nail involvement. Conclusions No single currently available treatment option sufficiently addresses all SAPHO-associated symptoms. Variable, sometimes descriptive outcomes and the use of treatment combinations complicate conclusions and treatment recommendations. Randomised clinical trials are necessary to generate reliable evidence.


INTRODUCTION
2][3][4] SAPHO is characterised by osteoarticular and dermatological features following a waxing and waning course with episodes of remission and exacerbation. 1 2 5SAPHO frequently affects the anterior chest wall and axial skeleton, but other regions may be affected. 1 3The clinical presentation is heterogeneous, with variable impact on quality of life due to pain, functional impairment and cosmetic alterations. 3 4 6-8While SAPHO typically affects adults, it can also be present in children and young people.Notably, because of overlapping clinical features, especially sterile osteitis, SAPHO may be closely related to chronic non-bacterial osteomyelitis (CNO), its severe form chronic recurrent multifocal osteomyelitis (CRMO), 2 3 5 and pustulotic

WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒ Synovitis acne pustulosis hyperostosis osteitis (SAPHO) is a syndrome encompassing musculoskeletal and dermatological manifestations, for which there are currently no agreed standard treatment protocols.

WHAT THIS STUDY ADDS
⇒ Observational and open-label clinical studies of treatments for SAPHO report upon a range of drugs including NSAIDs, bisphosphonates and diseasemodifying antirheumatic drugs.However, outcome measures vary and symptom control differs between patients, with a combination of therapies often being needed.

THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
⇒ Randomised controlled trials are needed to determine optimum treatment protocols that will address all manifestations of SAPHO.This will require the generation of internationally-agreed classification criteria and outcomes measures.
In the absence of reliable epidemiological data, a prevalence of <1/10 000 has been estimated. 10 11Reports from all geographic regions are available in the literature, and a female predilection (approximately 2.2:1) has been suggested (by at least 23 here included reports from European, Asian, African and Australian populations). 3 4 6 7 12-30n the current absence of widely accepted and independently validated diagnostic and classification criteria, diagnosing SAPHO relies on the presence of clinical features (including sterile bone inflammation, arthritis, inflammatory skin disease) and the exclusion of differential diagnoses (such as infections, tumours, Langerhans cell histiocytosis). 2Several sets of diagnostic or classification criteria have been proposed, of which the ones developed by, Kahn et al (1994 modified in 2003) and Benhamou et al are most commonly used across the literature (table 1). 9 31-35 Notably, classification criteria (other than diagnostic criteria) are developed to define clinically homogeneous disease cohorts for the inclusion in clinical trials.They are aiming for high specificity at the expense of sensitivity. 36Alongside radiographic imaging (plain radiographs, CT), bone scintigraphy, MRI, whole-body MRI and positron emission tomography (PET) CT are considered key diagnostic tools. 31Notably, scintigraphy is limited by high exposure to radiation, reduced ability to discriminate between growth plates and bone lesions (in young patients), and the inability to interpret extraosseous tissues. 37Plain radiographs and CT scans provide an understanding of structural changes and damage. 38MRI and PET CT enable early detection of bone lesions prior to structural damage, and provide information on soft tissue involvement. 31

Treatments Treatments Treatments
The exact molecular pathophysiology of SAPHO remains unknown.0][41] Because of clinical overlaps, some authors suggested that SAPHO may be a 'late stage' or the adult form of CNO/CRMO, and the result of ongoing innate immune activation that, over time, may result in the activation of adaptive immune mechanisms and pathological activation of effector T lymphocytes.Adaptive immune activation may, through the release of effector T cell-derived cytokines (such as IL-12, IL-17A, IL-23), result in the development of skin and nail changes frequently seen in SAPHO. 42 43ecause of overlapping features, such as skin and sacroiliac involvement, some authors also suggested that SAPHO may be closely linked to spondyloarthropathies, another effector T-cell-mediated disease.However, other than in spondyloarthropathies, a strong association with HLA-B27 has not been reported in SAPHO. 25 30Similar to CNO/CRMO in the paediatric population, associated autoimmune diseases among the SAPHO patients have been reported. 5 8 44onsidering clinical characteristics and suspected molecular and cellular mechanisms involved in CNO/ CRMO and SAPHO, several treatments have been suggested to control pain and inflammation.Treatments reported in the literature include antimicrobial agents, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, bisphosphonates, conventional diseasemodifying antirheumatic drug (cDMARDs) and biological (bDMARDs) 6 41 (figure 1).However, because of its rarity and the limited understanding of its molecular pathophysiology, evidence is limited to small open-label studies and case series.
This manuscript systematically reviews the available literature, including case series and clinical studies investigating treatment response in SAPHO patients (including five or more patients).

METHODS
This review was conducted in accordance with 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' guidelines for systematic reviews. 45

Eligibility criteria
Clinical studies (case series, prospective and retrospective cohort studies, clinical trials) discussing treatment Figure 1 The molecular pathophysiology and treatment options for SAPHO (adapted from Goenka et al). 43The exact aetiology of SAPHO is uncertain but likely links immune dysfunction with genetic predisposition and infectious triggers.Dysregulated activation of transcriptional regulatory factors (NFkB) and proinflammatory cytokines (IL-1, IL-6, IL-17, IL-23, TNF) results in dysregulated inflammatory responses and sterile osteitis.Proinflammatory cytokines IL-1, IL-6, TNF and IL-17, and prostaglandins (PG) promote osteoclast formation, resulting in increased bone remodelling.Furthermore, IL-17 may also be implicated in palmoplantar pustulosis (PPP) and psoriasis.Treatments reported in the literature target various molecular and cellular contributors to SAPHO.Antimicrobial agents target skin colonisation with Propionibacterium acnes.Biological TNF inhibitors (TNFi), IL-6 receptor blockers (IL-6i) and IL-17 inhibitors (IL-17i) limit inflammatory cytokine signalling, while JAK inhibitors (JAKi) may inhibit proinflammatory cytokine expression and the differentiation of effector Th17 T-cells.Bisphosphonates cause osteoclast apoptosis, thereby inhibiting bone resorption, but also have anti-inflammatory effects through the correction of imbalances proinflammatory and anti-inflammatory cytokine expression.Corticosteroids inhibit phospholipase A2 and COX enzymes, reducing PGs.Additionally, corticosteroids alter expression of NFκΒ-dependent proinflammatory cytokines.NSAIDs inhibit COX enzymes reducing PG production.Methotrexate (MTX) and sulfasalazine (SSZ) reduce proinflammatory cytokine expression. 39 43 56

Study selection
The study selection was performed by SWSL supported by CH.Records were identified and filtered to include English language publications only.Search results were exported to EndNote V.X9, duplicates were removed using the EndNote V.X9 duplicate finder tool.Records were then screened by title and abstract.Main reasons for exclusion were previously undetected duplicates, manuscript that did not report treatment outcomes, publications with fewer than five patients, and inappropriate manuscript types (including systematic reviews, metaanalyses and letters).Next, full text manuscripts were retrieved.Eligibility was assessed for each paper following the inclusion and exclusion criteria detailed.Only those meeting eligibility criteria were included for analysis.

Data collection
Relevant data were extracted including study design and observation period, aims, patient inclusion and exclusion criteria, number of participants, demographics, treatment(s), methods and reported outcomes, and adverse effects.Outcome measures were diverse and consequently presented as reported in each study.Paper strengths and limitations were considered alongside study type and methods to assign an evidence level.

Literature search
The existing literature mostly comprised observational studies reporting a diverse set of treatments considering variable (mostly descriptive) outcomes. 6 52Evidence from randomised controlled trials (RCTs) was limited to a Chinese study, which had to be excluded from this review due to publication language (Chinese). 53n initial search delivered 2290 records, of which 1123 manuscripts remained after removing duplicates and non-English publications that underwent title and abstract screening.Of these, 1080 manuscripts were excluded applying exclusion criteria.Remaining manuscripts (N=43) were accessed for a full-text screen.Thirteen publications were removed as they were conference abstracts without an associated full text manuscript (remaining N=30), and two additional publications were removed based on exclusion criteria.Finally, 28 studies were included in full-text review (figure 2).

Antimicrobial agents
Historically, infections (especially with Propionibacterium acnes) had been considered as a pathomechanistic feature of SAPHO. 8 52As a result, 85 patients from 6 studies were treated with antimicrobial agents none of which resulted in sustained remission 4 12 19 25 26 28 (figure 1).Azithromycin and doxycycline were used in several studies despite negative bacteriological bone cultures, likely to address skin colonisation associated with acne.Unsurprisingly, only a minority of patients (11/55, 20%) reported (timelimited) symptomatic improvement. 4 12 19 26 28In patients with positive bacterial cultures for P. acnes in bone biopsies, RMD Open RMD Open RMD Open antimicrobial treatment improved osteitis lesions and reduced skin disease activity after 16 weeks.However, disease activity returned to baseline following discontinuation of antimicrobial treatment. 25In one study, despite negative or unknown bacterial cultures for P. acnes, antimicrobial therapy with clindamycin in combination with NSAIDs (below) resulted in clinical improvement with persistent pain resolution (4/4, 100%) and improved imaging findings (osteosclerosis n=2; osteitis n=2; osteolysis n=1) after 3 months or 4 months treatment.Another patient had resolution of sternoclavicular joint swelling and tenderness after 8 months of treatment. 4However, it remained unclear whether effects were due to antimicrobial agents and/or NSAIDs.
Only few and mild adverse effects were reported, including not further specified 'intolerance' (doxycycline n=2; azithromycin n=1). 12 25n-steroidal anti-inflammatory drugs NSAIDs are frequently used in rheumatology to modulate pain, inflammation, and osteoclast activity through inhibition of prostaglandin synthesis 41 55 56 (figure 1).Across studies, NSAIDs were usually used as first-line treatment to provide pain relief in SAPHO. 6 8 52A small proportion of SAPHO patients achieved partial or full remission in response to NSAID treatment alone, including 20% (4/20) of patients in a small Belgian cohort. 2 5 12 19 26 29 30 The majority of studies, however, reported inadequate effects or incomplete improvement. 5 21 30Of those studies, reporting efficacy of NSAIDs, most focused on pain reduction. 2 4 6 8 28One study also reported improved radiological and dermatological features (in addition to pain resolution) in patients treated with a combination of the antimicrobial agent clindamycin and lornoxicam. 4ide effects of NSAIDs included gastrointestinal symptoms, but no severe toxicity. 21 26rticosteroids Corticosteroids inhibit phospholipase A, which results in reduced prostaglandin E production affecting pain, inflammation and osteoclast function.Furthermore, they alter the expression of NFκB-dependent proinflammatory cytokines and enhance anti-inflammatory cytokine expression (including IL-10) 41 56 (figure 1).Long-term use of corticosteroids is limited by side effects that, among others, include loss of bone density, thinning of skin, weight gain and the development of iatrogenic Cushing's syndrome, infections, etc. 57 Corticosteroids can be applied systemically or locally (topical use on the skin, joint injections). 52cross 7 studies, a total of 56 SAPHO patients were treated with corticosteroids.Topical corticosteroids were used for dermatological manifestations, with psoriasis vulgaris resolution in one case when taken alongside adalimumab and eosin. 5Intra-articular corticosteroid injections were reported by four studies.Three studies suggested intra-articular corticosteroids to be effective, providing greater osteoarticular improvement when compared with oral therapy. 12 17 26One study failed to identify positive effects on osteitis (p=0.06) using 20 mg intra-articular triamcinolone but suggested benefit for arthritis management. 17ystemic corticosteroids were used with transient and/ or partial improvement in 26 individuals from three studies. 2 26 29Favourable outcomes were reported in individuals when corticosteroids were given in combination with either adalimumab (psoriasis vulgaris resolution, 1/1), Tripterygium wilfordii Hook F (a traditional Chinese herb with immunosuppressive effects: muscle oedema regression, 4/4; subcutaneous soft tissue swelling regression, 1/1; bone marrow oedema (BMO) regression, 2/4; periosteitis regression, 1/2; temporomandibular joint synovial thickening regression, 3/3) or methotrexate (cortical/medullary lysis on CBCT, 1/1). 5 23In a small Chinese cohort, corticosteroid monotherapy led to regression of muscle and BMO (both 2/3, 66.7%), subcutaneous soft tissue swelling (1/1) and temporomandibular arthritis (1/1). 23hile no adverse events or severe side effects were reported in these included studies, long-term follow-up is lacking, and concerns remain in relation to drug safety and recognised corticosteroid-associated complications. 58sphosphonates Bisphosphonates inhibit osteoclast-mediated bone resorption and have anti-inflammatory effects, reconstituting the balance between proinflammatory and antiinflammatory cytokines. 3 6 7 13 15 52A total of 176 patients were treated with bisphosphonates across 17 studies.Notably, reported effects of bisphosphonates are mostly limited to bone inflammation with no consistent improvement of cutaneous lesions across the literature. 59 60reatment with bisphosphonates improved osteoarticular disease in a majority of patients across studies. 2 3 6 7 12 13 15 16 19-21 23 26 29 30 This included patients refractory to NSAIDs and corticosteroid injections. 12 13 26ctive agents, administration methods and doses vary between studies (table 2).Four manuscripts did not disclose specific bisphosphonates used, route of administration, nor dose. 23 26 29 30 Where available, MRI confirmed rapid and sustained improvement of spinal BMO in two studies including 44 patients (for 37 of whom MRI studies were available). 7 23Somewhat unexpectedly, one open-label study also reported beneficial effects of pamidronate on skin lesions, preventing recurrence of pustulosis in 9/10 patients (90%) refractory to oral corticosteroids, colchicine, methotrexate, sulfasalazine or infliximab. 13However, NSAID use was permitted as concomitant treatment, which may have had additional effects. 13Others did not confirm effects on the skin. 15cross studies, pamidronate was the most frequently chosen bisphosphonate (n=122/176 patients, 69.3%; 12/17 studies, 70.6%).Pamidronate was effective in early disease, but may also have a role in late-stage otherwise Treatments Treatments treatment refractory SAPHO. 15 16Intravenous pamidronate effectively controlled osteoarticular lesions, with most patients experiencing partial or complete pain control. 13 15 16 19 20Some studies reported reduction of osteolytic lesions coinciding with complete clinical, laboratory and radiological remission. 2 23In one study, pain relief was associated with reduced need for other medications, including NSAIDs. 16A study in paediatric SAPHO patients suggested persistent effects of pamidronate with improved activity and well-being. 3hough not included across all international treatment plans for paediatric CNO/CRMO because of lacking information on anti-inflammatory effects, 61 62 alendronate and zoledronic acid have been used in SAPHO in a Chinese study and an Australian study. 6 54Symptomatic relief has been reported in 16/18 (88.9%) patients in the Chinese study (70 mg alendronate per week (15 recipients) or 5 mg zoledronate annually (3 recipients).However, the benefit from bisphosphonate alone is difficult to ascertain as 17/18 (94.4%) received concomitant therapy with NSAIDs, DMARDs, low-dose corticosteroids or TNFi. 6Alendronate monotherapy was effective in one Australian patient. 6Three patients from the same study received either pamidronate or zoledronic acid, which did not improve bone involvement. 54isphosphonate associated side effects were in line with previous reports and included influenza-like symptoms and/or timely limited feverish episodes, 3 5 7 12 16 headaches and mild hypocalcaemia 7 in patients receiving pamidronate.Gastrointestinal disturbances were infrequently reported in Chinese cohorts.However, one patient received cDMARDs alongside alendronate. 6 7Notably, one study from Italy reported no side effects in a cohort of 14 patients. 15Taken together, bisphosphonates appear safe and promising, particularly with spinal BMO. 7 23 54nventional (non-biologic) DMARDs cDMARDs are usually used when symptoms persist despite NSAID treatment. 52Across 10 studies, 173 patients were treated with variable effects.Methotrexate and sulfasalazine reduce inflammatory cytokine expression, thus potentially correcting the imbalance between proinflammatory and anti-inflammatory signals. 63Methotrexate and sulfasalazine were most commonly used. 6 12 19 23 26-30 54wo studies reported colchicine use (in 34 patients) with little or no improvement. 12 26Azathioprine, leflunomide and cyclosporine were reported in a few individual patients. 6 29 30 54Other studies suggested that using NSAIDs or corticosteroids alongside methotrexate may be more effective than methotrexate alone. 6 23 29Overall, complete inefficacy of methotrexate was relatively uncommon (11/54 patients Single infusion (30 mg) Van Doornum et al 21 Single infusion per course (60 mg) Amital et al § 13 Infusion of 60 mg/day for three consecutive days Colina et al 15 Guignard et al 16 ¶ Solau-Gervais et al 15 16 20 Single infusion per course (180 mg) from 6 studies, 20.4%). 6 12 19 26 29 54Among these, 8/13 patients relapsed following good initial response, 54 and 2 switched to other cDMARDs without additional benefit. 29ulfasalazine was associated with minimal or partial improvement of pain, palmoplantar pustulosis and acne. 12 26Some patients refractory to NSAIDs experienced resolution of osteoarticular pain. 19One patient had over 17 years sustained benefit as demonstrated by Physician Global Assessment scores. 54verall, cDMARDs were tolerated without severe side effects.Most publications did not report side effects beyond gastric discomfort in patients receiving methotrexate or sulfasalazine. 6One study suggested that methotrexate (without concomitant corticosteroids) may be associated with metabolic syndrome. 28ological DMARDs bDMARDs are used in otherwise treatment refractory patients.Cytokine blocking strategies are used to (at least partially) correct the cytokine imbalance associated with SAPHO (figure 1). 2 5 6 12 14 19 23 24 27 29 30 54 64 A total of 90 patients from 11 studies were treated with TNFi.Overall, reported effects were positive. 6 14 19 27 54In one case where adalimumab lost efficacy with worsening skeletal and cutaneous symptoms after initial pain and palmoplantar pustulosis improvement, add-on cDMARD therapy with methotrexate, sulfasalazine and eventually cyclosporine led to symptom relief. 6Reports of inefficacy were few (n=5/90, 5.56%), 6 12 14 29 and included an individual who had initial clinical response but ultimately had to add on cDMARD treatment 6 and two patients who initially benefited from infliximab before switching to alternative TNFi for recurrence of bone pain. 14ost studies reported partial or complete clinical response, including reduction of pain, disease activity as measured with BASDAI and other osteoarticular presentations including sacroiliitis. 2 5 6 14 30 54 64Skin improvement was described in four Chinese individuals. 64The use of etanercept was associated with complete clinical and laboratory/imaging remission in most patients of a small Chinese cohort (7/10, 70%), but did not allow discontinuation of concomitant therapy in a French study. 2 27 Improvement was sustained across several studies, including pain control following treatment discontinuation, 64 and preventing joint and spinal damage progression (8/11; 73%) of patients continuing treatment for at least 1 year. 54Infliximab led to persistent physician-assessed benefit for 3 years in one individual. 12dalimumab remained efficacious with reduced BASDAI for 22 months in another individual. 14ide effects were rare in patients treated with TNFi.Nine cases (9/90, 10%) of psoriasiform lesions were noted across two studies, including paradoxical psoriasis, existing palmoplantar pustulosis exacerbations and urticaria. 14 64Late onset of skin manifestations during the disease course were associated with increased risk of exacerbated lesions under TNFi in the Chinese study. 64Most paradoxical lesions resolved after discontinuing TNFi and introduction of non-biological therapy. 14 64However, at least some of these potential adverse events may have been associated with the natural course of disease in some patients as SAPHO is associated with psoriasiform skin disease.
Additional cytokine blocking agents targeting IL-6 (a factor during effector Th17 T-cell differentiation) or the IL-23/IL-17 axis have been considered for SAPHO because of clinical overlaps with psoriasis and spondylarthritis. 23 24 54Nine patients were treated across three studies from China, France and Australia.Blockade of the IL-6 receptor with tocilizumab failed to induce bone lysis remission on CT in a Chinese SAPHO patient. 23utcomes in response to IL-17 blockade with secukinumab or ixekizumab were disappointing as none of the three Australian patients reached full and sustained remission. 54Ustekinumab targets IL-12/23 and led to cutaneous benefit in 33.3% (1/3) of a small French cohort but was not reported to benefit bone features; secukinumab had benefited 66.7% (2/3) who had not received ustekinumab in the same study. 24One case of paradoxical psoriasis (2/9 patients, 22.2%) was reported for each secukinumab and ustekinumab. 24otein kinase inhibitors JAKs are involved in cytokine receptor signalling, and the differentiation and activation of effector Th17 cells (figure 1).Because of clinical overlaps between SAPHO, psoriasis and spondyloarthropathies, they may be promising treatment options in patients refractory to other treatments.
One study investigated effects of the JAK inhibitor tofacitinib on dermatological manifestations in 13 Asian female SAPHO patients (12 weeks of 5 mg tofacitinib, twice daily). 18Results were positive with significant benefit for nail lesions, palmoplantar pustulosis and associated quality of life.While a reduction of systemic inflammatory parameters was observed (CRP and ESR), no information was provided on bone involvement.
One patient experienced acute tonsillitis during the treatment period.No severe adverse events were reported.

Other treatments
Tripterygium wilfordii Hook F is a Chinese herbal medicine used to treat immunological disorders. 6 22The mechanisms underlying its effects are diverse and remain largely unknown.It has been suggested to affect effector T-cell function, monocyte phenotypes, and proinflammatory and anti-inflammatory cytokine expression. 65Lacking regulatory approval, its potential toxicity and side effects limit clinical applications in the Western world.Three Chinese studies reported 41 SAPHO patients treated with Tripterygium wilfordii Hook F. Treatment associated with improved disease activity (measured by ASDAS and BASDAI) and reduced pain when compared with baseline across two small cohorts. 22 23Results were less convincing in the third study, including lack of response Treatments Treatments Treatments in one patient. 6Only one of the three reported side effects with elevated transaminases (ALT levels) in 14/30 patients (46.7%), of whom one individual had to stop treatment. 22n addition to systemic anti-inflammatory treatment, three studies reported patients receiving topical treatments for skin involvement, including psoralen in combination with ultraviolet light radiation (PUVA), retinoids (systemically or topically), betamethasone and calcipotriol (a vitamin D derivative containing ointment). 4 26 30Of the two studies reporting patient numbers, four patients were treated, however, treatment efficacy was only discussed in one patient reporting palmoplantar pustulosis improvement following treatment with topical corticosteroids and PUVA. 4 Lastly, Xiang et al suggested a possible association between tonsillectomy and improved cutaneous and osteoarticular manifestations, as ostealgia and palmoplantar pustulosis significantly improved with reduced VAS and PPPASI scores in 6/7 and 6/6 patients, respectively. 66

DISCUSSION
The molecular and cellular pathophysiology of SAPHO is incompletely understood, complex and likely multifactorial, involving genetic predisposition and environmental impacts. 52Our current, limited understanding suggests a combination of dysregulated innate and adaptive immune mechanisms resulting in clinically variable pictures characterised by skin and bone inflammation. 42hile some reports suggested the presence of P. acnes in bone lesions, 52 these likely represent skin contaminants. 67Indeed, P. acnes is a common skin contaminant across biospecimen, especially in adults. 68However, P. acnes may still affect disease expression and phenotypes as a skin commensal.It may contribute to proinflammatory cytokine expression, including TNF, IL-1, IL-8 7 52 and the IL-23/Th17 axis. 52Based on studies primarily in paediatric CNO/CRMO, bone inflammation in SAPHO is thought to result from disrupted innate immune mechanisms, including NRLP3 inflammasome expression and assembly.Imbalanced cytokine expression may increase osteoclast activity and bone remodelling. 56Skin disease, on the other hand, may be the result of adaptive immune dysregulation and the differentiation and activation of effector T cell phenotypes. 39 43s a result, several classes of drugs have been applied in SAPHO to control inflammation: ► Antimicrobial agents have been considered because of reports (incorrectly) suggesting P. acnes as a causative pathogen 4 12 19 25 26 28 or a contributing environmental factor. 52Unsurprisingly in an autoimmune/ inflammatory disease, antimicrobial agents were largely ineffective, especially long-term after their discontinuation.Initial improvement in some patients may have been due to immunomodulating effects. 25 NSAIDs have been used because of their analgesic effects.They also have (mild) effects on inflammasome assembly and osteoclast activation. 55 56While NSAIDs provide pain relief, they are less effective in extensive bone involvement and for the treatment of skin inflammation. 52Thus, they may be applied as first-line treatment in the absence of contraindications and supplemented by add-on therapies if not effective.► Corticosteroids reduce prostaglandin production by inhibiting phospholipase A2, thereby inhibiting osteoclast activity.Furthermore, corticosteroids reduce the expression of proinflammatory NF-κB-regulated genes while increasing the expression of immunoregulatory cytokines. 56While long-term use is prohibited by side effects, they can be considered for induction of remission and/or as bridging therapy, for example, until cDMARDs are developing efficacy.► Bisphosphonates have been used to treat SAPHO for their effects on osteoclasts and their ability to correct cytokine imbalances. 3 7 13 15 52 56Bisphosphonates, especially pamidronate, may additionally suppress production of IL-1β, IL-6 and TNF, reducing chronic inflammation. 3 7 13 15 52Bisphosphonates were particularly effective to reduce pain and terminate bone inflammation in SAPHO, while no convincing effects were seen on skin inflammation. 7 12 13 15 23 26 29 30► The cDMARDs methotrexate and sulfasalazine can correct proinflammatory and anti-inflammatory cytokine imbalances and have, therefore, successfully been used for the treatment of chronic arthritis and inflammatory skin diseases. 56Several reports on the use of methotrexate for bone and skin involvement in SAPHO suggest efficacy, 19 26 54 while sulfasalazine delivered less promising results. 12 26► Several bDMARDs have been used to (partially) correct the cytokine imbalance associated with SAPHO. 43 69TNF is a proinflammatory cytokine implicated in autoimmune dysfunction and dysregulated osteoclast function. 64 69TNFi correct proinflammatory and immune modulatory cytokine imbalances.They have been successfully used for the treatment of clinically related psoriasis and spondylarthropathies. 2 5 6 14 27 30 54 64 In SAPHO clinical benefits of TNF inhibitors include resolution of bone inflammation and associated pain as well as skin disease. 56In addition to TNF, also IL-17 and IL-23 have been implicated in related autoimmune conditions and may be involved in osteoblast differentiation, pathological bone remodelling and skin involvement in SAPHO. 69Somewhat unexpectedly, limited reports on IL-17 (secukinumab, ixekizumab) and IL-12/23 (ustekinumab) blockade documented limited effects on both bone and skin inflammation in SAPHO. 24 54Similarly, blockade of IL-6 signalling, a cytokine involved in effector Th17 cell differentiation, had limited effects. 23otably, most aforementioned treatments, individually, had limited effects on all organ systems affected.Especially effects on cutaneous manifestations of SAPHO were somewhat disappointing.Thus, one study examined RMD Open RMD Open RMD Open the JAK inhibitor for the treatment of cutaneous lesions, nail changes and associated quality of life without severe adverse effects. 18As dermatological lesions are associated with psychosocial burden, it's necessary to further explore the role of JAK inhibitors.
Notably, treatment regimens varied not only between studies but also between geographic regions (table 3).While no obvious differences in relation to geographical region (associated predominating ethnicities) and treatment responses were identified, differential effects may still be present.Notably, three Chinese studies investigated effects of Tripterygium wilfordii Hook F, an antiinflammatory herb that acts through several compounds including triptolide. 22Lacking medical licensing in Western medicine, unknown mechanisms of action, and an incompletely understood side effect spectrum preclude this medication from routine use.
1][72] To address these limitations in SAPHO, we defined the evidence levels of studies included in this systematic review using definitions suggested by Ackley et al (table 4). 73Of the 28 studies included here, 20 were observational in nature, and 8 were open-label clinical trials.As a result, evidence levels assigned were overall relatively low (level 6: n=19; level 4: n=1; level 3: n=8).Robust evidence from RCTs is lacking (online supplemental tables S4 and S6).
Further key challenges with data interpretation include the absence of internationally agreed case definitions, consistent inclusion/exclusion criteria, defined and validated disease-specific outcome measures, aforementioned small patient numbers, and the frequent use of concomitant treatments that are likely caused by the clinical variability of disease and multiple organ involvements that require various treatments (frequently in combination).
A potential limitation of this review relates to inconsistent nomenclature across the literature, which may have led to the exclusion of studies.Because of the broad clinical spectrum and inconsistent nomenclature (including 'adult CNO/CRMO', 'PAO', 'sternocostoclavicular hyperostosis (SCCH)', etc, which may be limited forms of SAPHO or related disorders), only manuscripts reporting cohorts of 'complete' SAPHO patients were considered.Notably, manuscripts reporting CNO/ CRMO were not included because it is currently under debate whether CNO and SAPHO are distinct entities. 9 47 48Although the authors argue that CNO/CRMO and SAPHO may be considered 'extremes' on a spectrum of inflammatory bone diseases, and SAPHO may represent a 'late stage' presentation of CNO/CRMO, this systematic review focused on 'complete' SAPHO syndrome. 43 47 48 51Indeed, in a recent review, Leerling et al described adult CNO/CRMO as a subtype within a wider disease spectrum.Authors report that the presence of joint and skin pathology increases the likelihood for physicians to distinguish SAPHO from CNO.Because approximately 50% of physicians managing adult CNO/ CRMO distinguish between CNO/CRMO and SAPHO, some SAPHO patients in the literature may have been missed in the systematic review presented here. 47Therapeutic approaches to CNO/CRMO are summarised

Treatments Treatments Treatments
and discussed elsewhere, and similarities exist in the treatment across the CNO/CRMO/SAPHO spectrum usually with considered first-line treatment options, and cDMARDs (eg, methotrexate or sulfasalazine), bisphosphonates and TNFi reserved for severe and/or treatment-refractory cases. 41 47 48 56Similarly, opinions vary whether SAPHO and PAO constitute the same disease. 9 46 49 50Proposed PAO criteria (Sonozaki et al 74 ) differ from commonly used SAPHO criteria (summarised in table 1) in that PAO can be limited to PPP and CNO. 46This supports the proposal of PAO being a subset within SAPHO, with patients with only PPP and arthralgia sometimes being treated as SAPHO. 49 50hese clinical differences were a key argument for Yamamoto when suggesting to distinguish PAO and SAPHO. 49otably, the term PAO has primarily been used in reports from Japan, 47 potentially suggesting contrasting presentations of CNO/CRMO/SAPHO spectrum disorders between Western and East Asian cohorts. 50 51Notably, PAO patients (other than CNO/CRMO and SAPHO patients reported in Western cohorts) frequently experience concurrent focal infections, such as tonsillitis and/ or arthro-osteitis, 46 50 which results in surgical approaches to treatment, for example, tonsillectomy. 50 75 76Distinct treatments included iodide, 77 granulocyte and monocyte adsorption apheresis. 78Despite this, treatment similarities are seen, with a multicentre study showing many receiving NSAIDs, cDMARDs and antimicrobials. 50This is reflected in other papers treating with cyclosporine 50 79 and adalimumab. 801][82] Similar arguments have been made around SCCH being a SAPHO subset and part of the CNO spectrum, and two cases have been reported with success in pain and functional improvement. 83ain scores (VAS) were commonly reported which are complicated by subjective pain experiences of individual patients and a multidimensional experience of pain that may vary between SAPHO patients with comparable disease activity. 84Potentially more objective outcome measures include laboratory tests for inflammatory markers.However, systemically increased inflammatory parameters, clinical disease activity and disease burden do not correlate closely in all patients. 14 25 66Lastly, differences between ethnic groups (with differential representation between geographical regions) and sexes have also not been considered in studies available to date.Considering ethnic diversities in some Western countries especially, ethnicity across study populations cannot be simply estimated, which limits reliable conclusions in relation to associations between ethnicity and outcomes.

CONCLUSIONS
Several treatment options exist for SAPHO, however none of them are equally effective for all organ systems involved.The absence of internationally agreed and validated diagnostic and classification criteria as well as agreed outcome measures, the small sample size of studies, and variable therapeutic approaches, with many patients requiring multiple treatments, challenge data interpretation and recommendations.Bisphosphonates may achieve rapid remission of bone inflammation and associated pain, cDMARDs and TNFi are effective for bone and (to some extent) skin involvement, while JAKi may be an option especially in otherwise treatment refractory skin and nail involvement.Further studies (especially double blinded prospective RCTs) are urgently needed to improve the evidence base of SAPHO treatment.
Contributors SWSL and CH contributed equally to all stages of manuscript preparation.ER was invovled in literature search, data collection and writing of the revised final version.

Figure 2
Figure 2 PRISMA diagram displaying search results, exclusion and inclusion of manuscripts. 45PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1
Proposed criteria for SAPHO ► Usually sterile ► Spine may be involved ► With or without skin condition Acute, subacute, or chronic arthritis associated with any of the following: ► Palmoplantar pustulosis ► Pustular psoriasis ► Severe acne Any sterile (or with presence of Propionibacterium acnes) osteitis (one localisation is sufficient, including spondylodiscitis) associated with any of the following: ► Palmoplantar pustulosis ► Pustular psoriasis ► Psoriasis vulgaris ► Severe acne ► Bone/joint involvement associated with palmoplantar pustulosis and psoriasis vulgaris ► Bone/joint involvement associated with severe acne ► Isolated sterile (except P. acnes) hyperostosis/osteitis (adults) ► Chronic recurrent multifocal osteomyelitis (children) ► Bone/joint involvement associated with chronic bowel diseases ► Infectious osteitis ► Tumours of bone ► Osteoarticular manifestations of severe acne ► Osteoarticular manifestations of palmoplantar pustulosis ► Hyperostosis with or without dermatosis ► ► Possible association with psoriasis vulgaris ► Possible association with inflammatory enterocolopathy ► Features of ankylosing spondylitis ► Presence of low virulence bacterial infections SAPHO, synovitis acne pustulosis hyperostosis osteitis.

Table 2
Bisphosphonate use across studies

Table 3
Treatments studied by geographical region

Table 4
Definitions of evidence levels