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This review brings together the largest body of clinical experience to date on modern treatments for SAPHO syndrome, a rare and often difficult‑to‑manage condition lacking formal guidelines. By analyzing outcomes from over 100 published reports, we show that some therapies commonly used in other rheumatic diseases—particularly tumor necrosis factor inhibitors and Janus kinase inhibitors—may provide meaningful relief of skeletal and skin symptoms when other treatments fail. Other targeted drugs, such as interleukin 17 or interleukin 23 inhibitors, show more variable benefit, highlighting the need to match therapy to individual patient profiles. This paper underscores the urgent need for coordinated research efforts, including prospective registries and randomized clinical trials that can transform fragmented case‑based knowledge into evidence‑based care.

Introduction

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare disease (estimated incidence in white patients about 1:10 000; ORPHA code, 793) characterized by the coexistence of osteoarticular inflammation and neutrophilic skin disease, most commonly palmoplantar pustulosis and acne.¹ The etiology remains unclear, but infectious triggers, genetic predisposition, and dysregulated innate and adaptive immune responses appear to contribute to the disease development.² Due to frequent axial involvement and associations with psoriasis and inflammatory bowel disease, SAPHO syndrome is conventionally classified as an autoimmune disease within the spondyloarthritis (SpA) spectrum. On the other hand, neutrophil hyperactivity, reduced level of natural killer cells, elevated levels of proinflammatory cytokines, and clinical similarities with several monogenic autoinflammatory syndromes may indicate autoinflammatory origin.³ Typical manifestations include anterior chest wall osteitis—particularly of the sternoclavicular joints—sacroiliitis, spinal inflammation, palmoplantar pustulosis, peripheral arthritis, and severe acne.^4-8 The most widely used classification system, that is, the 2003 modified Kahn criteria,¹ also encompass chronic recurrent multifocal osteomyelitis (CRMO), the pediatric form of chronic nonbacterial osteomyelitis, as part of the SAPHO spectrum.

Recently, international expert consensus recommendations⁹ have proposed the term adult chronic nonbacterial osteomyelitis (CNO) to harmonize terminology for inflammatory bone disease in adults and align it with the pediatric CNO/CRMO spectrum. However, much of the existing clinical literature—including most therapeutic reports—has historically used the broader concept of SAPHO syndrome, which encompasses both osteoarticular inflammation and associated neutrophilic skin disease. As the studies included in this review predominantly employ the SAPHO terminology and frequently describe patients with combined osteoarticular and cutaneous manifestations, we retain the term SAPHO in the present analysis while acknowledging its conceptual overlap with adult CNO.

SAPHO syndrome substantially impairs quality of life through chronic pain and functional limitations, and may lead to local bone destruction, most often in the sternoclavicular region.⁸ Despite this burden, no approved therapies or standardized care guidelines exist.^10,11 Due to the rarity of the condition, treatment recommendations are based almost entirely on case reports and single‑center experiences. The only randomized clinical trial (RCT) to date evaluated pamidronate vs placebo in patients with CNO, but probably due to the small sample size, not all end points reached significance.¹²

Conventional treatments used in other conditions from the SpA spectrum—nonsteroidal anti‑inflammatory drugs (NSAIDs), conventional synthetic disease‑modifying antirheumatic drugs (DMARDs; eg, methotrexate, sulfasalazine), and systemic or local glucocorticoids—are commonly used in SAPHO,^4-6,8 yet only about one‑third of the patients achieve complete remission.¹³ These limitations have prompted growing interest in biologic and targeted synthetic DMARDs (b/tsDMARDs).

This therapeutic rationale is supported by accumulating evidence of dysregulated innate and adaptive immune signaling in SAPHO pathogenesis. Studies of serum cytokine profiles, lesional tissue, and experimental models suggest activation of neutrophil‑driven inflammation together with aberrant osteo‑immune interactions involving tumor necrosis factor (TNF), interleukin 1β (IL‑1β), IL‑6, and the IL‑23/IL‑17 axis.^2,3,10,11 TNF promotes osteitis and synovitis through recruitment of neutrophils, activation of macrophages and T cells, and stimulation of osteoclast differentiation. IL‑1β and IL‑6 amplify inflammatory cascades by enhancing cytokine production and immune cell differentiation and by promoting osteoclastogenesis and bone resorption.^2,3,11 The IL‑23/IL‑17 pathway appears particularly relevant to the coexistence of osteoarticular and cutaneous manifestations, as IL‑17 contributes to neutrophil activation, chronic tissue inflammation, and dysregulated bone remodeling, including impaired osteoblast function.^2,3,11 Increased expression of these cytokines has been demonstrated in peripheral blood and inflammatory lesions in SAPHO and related autoinflammatory bone disorders, supporting a biologically plausible rationale for targeted therapy.^2,10 These mechanistic insights have guided the off‑label use of bDMARDs targeting TNF, IL‑1, IL‑6, IL‑17, and IL‑23 in patients with refractory disease.^10,11 In addition, Janus kinase inhibitors (JAKis) offer a broader therapeutic approach by blocking intracellular signaling of multiple proinflammatory cytokines via the JAK/signal transducer and activator of transcription pathway, which integrates signals from several cytokine families implicated in SAPHO pathophysiology, and may therefore affect both osteoarticular and cutaneous disease domains.^3,11

Although targeted therapies have been increasingly reported, the evidence base remains limited to isolated case reports and small case series. No completed RCTs exist, although an RCT evaluating etanercept in SAPHO is currently underway (Study of the efficacy and safety of etanercept treatment in patients with SAPHO syndrome; NCT06011889). Two systematic reviews have been published: the one from 2019 focused mainly on TNFis and did not include IL‑17/IL‑23 inhibitors or JAKis¹⁴; and another from 2023 excluded studies with fewer than 5 cases, studies lacking safety outcomes, and those involving patients with isolated CRMO/CNO.¹¹ Given that the modified Kahn criteria⁹ include nonbacterial osteitis as part of the SAPHO spectrum, such exclusions may substantially limit evidence synthesis in a rare disease.

The objective of this systematic review was to comprehensively evaluate the efficacy of b/tsDMARDs in SAPHO syndrome, including CRMO/CNO and case reports, across clinical and, where available, radiological outcomes, regardless of comparator or outcome definitions.

Patients and methods

This systematic review was conducted in accordance with the PRISMA guidelines,¹⁵ with predefined modifications appropriate for evidence derived predominantly from case reports and case series.

Results

The database search identified 1598 records, with an additional 17 identified through reference screening. After the removal of duplicates, 1610 records were screened by title and abstract, and 179 full texts were retrieved and assessed for eligibility. Five potentially relevant reports could not be retrieved due to a lack of library access (listed in Supplementary material), and 3 were excluded due to a lack of full text. The final review included 106 studies (listed in Supplementary material) describing 385 cases of b/tsDMARD use in SAPHO. The flow diagram of full systematic literature search results is presented in Figure 1.

No results of RCTs were found. A single post hoc analysis of a phase 3 randomized, double‑blind, placebo‑controlled trial of guselkumab in Japanese patients with palmoplantar pustulosis included a subgroup with pustulotic arthro‑osteitis fulfilling SAPHO criteria. All remaining studies were case reports or case series. The results of the review are synthetized in Figure 2.

Demographic data were inconsistently reported across studies. Summary statistics were calculated only for patients with available age and sex information. In the patients with available information, the median (interquartile range [IQR]) age was 41 (27–49) years for TNFis, 38 (29.5–45.5) years for JAKis, 39 (32.5–49.8) years for IL‑17 inhibitors (IL‑17is), 43 (35–54) years for IL‑23is, and 48 (39.5–53) years for other targeted therapies. Women predominated in most treatment groups (56.8%, 70%, 71.4%, and 87.5% respectively), except for the small group receiving other targeted therapies (45.5%).

Both adult and pediatric patients were represented, reflecting the inclusion of CRMO/CNO within the SAPHO spectrum. Pediatric patients were rarely represented in the included reports. Based on available age data, 10 cases involved patients younger than 18 years. Most pediatric cases were treated with TNFis (n = 7). Two pediatric cases treated with a JAKi and 1 case treated with an IL‑1i were also identified. Due to the small number of pediatric cases and heterogeneous reporting, no separate analysis of treatment outcomes in children was feasible.

Discussion

This systematic review, encompassing 106 studies, highlights the growing use of b/tsDMARDs in the treatment of SAPHO syndrome. The 2019 systematic review identified only 66 cases of patients treated with bDMARDs.¹⁴ Our systematic review describes 385 cases treated with b/tsDMARDs. As the earliest biologic class introduced in rheumatology, TNFis are the most frequently reported in SAPHO. In the absence of contraindications, they appear to be a reasonable first‑line biologic option for patients who do not respond to conventional therapies. The ongoing RCT evaluating etanercept may help substantiate this approach and provide much‑needed evidence‑based guidance.

JAKis represent the second most extensively documented therapeutic class, and have shown high complete response rates in available case reports and series. Their broad mechanism of action—blocking intracellular signaling downstream of multiple proinflammatory cytokines—may be advantageous in a disease as immunologically complex as SAPHO.^2,3,11 In contrast, the inhibitors targeting individual cytokines (IL‑1, IL‑6, IL‑17, or IL‑23) showed more variable efficacy. This heterogeneity of response likely reflects the multifactorial cytokine network underlying SAPHO pathogenesis rather than the dominance of a single inflammatory pathway.^2,3,10 Nevertheless, given anecdotal evidence of partial benefit, these agents may serve as reasonable alternatives in cases of inadequate response, intolerance, or contraindications to TNF or JAK inhibition.

Recently published international consensus recommendations have proposed the term adult CNO and outlined a treatment approach based primarily on NSAIDs, TNFis, and bisphosphonates.⁹ However, these recommendations are largely based on expert consensus and limited clinical evidence. The present review complements the recommendations by summarizing the accumulated case‑based experience with b/tsDMARDs reported in patients historically classified as having SAPHO syndrome. These data highlight that, in the patients with refractory or chronic disease, clinicians have explored a broader range of targeted therapies than those currently emphasized in the consensus recommendations. Importantly, many cases included in our review presented with a broader SAPHO phenotype, including cutaneous manifestations, indicating that the SAPHO concept remains clinically relevant for a substantial proportion of reported patients.

An important observation from this review is the limited and inconsistent reporting of radiological outcomes. Although imaging improvement of osteitis or bone marrow edema was described across several therapeutic classes, these data were available only for a small subset of cases and were assessed using heterogeneous modalities. In several reports, clinical improvement did not correspond with imaging findings, highlighting the complexity of disease assessment in SAPHO syndrome. The significance of radiological response as a measure of treatment effectiveness remains unclear. These observations underscore the need for standardized radiological outcome measures in future studies.