Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome may present with extra‐articular and cutaneous manifestations

SAPHO syndrome is a rare autoinflammatory disease that manifests with articular and cutaneous symptoms. Although epidemiological data on SAPHO are limited, the annual incidence of the disease is estimated to be 1 in 10 000 in Caucasians and 0.00144 in 10 000 in Japanese.1 The precise pathogenesis of SAPHO syndrome remains elusive, but it is hypothesized to have a genetic basis, linked to underlying infections and immune dysfunction. SAPHO syndrome is commonly recognized as a distinct pathological condition by researchers. However, some researchers have suggested that SAPHO syndrome can be classified as a form of spondyloarthritis, a potential transitional stage between ankylosing spondylitis (AS) and psoriatic arthritis.2, 3 Both SAPHO syndrome and spinal arthritis affect the axial and sacroiliac joints in a similar manner, exhibiting shared characteristics and even instances of co-occurrence.4, 5 SAPHO syndrome may be associated with the HLA-B27 gene.2 Patients with AS have multisystemic damage such as the heart, lungs, kidneys, eyes, intestines, skin, and bones through the support of a large number of data.6 Common extra-articular manifestations in AS include uveitis, inflammatory bowel disease, and psoriasis. These symptoms are also found in SAPHO syndrome in addition to the articular and cutaneous manifestations. The inaugural documentation of pleural effusion in conjunction with SAPHO syndrome was presented by Dumolard et al.7 Since then, a total of seven cases exhibiting pleural effusion in association with SAPHO syndrome have been reported, with only one patient experiencing recurrent pleural effusion.8 Sternal inflammation may be the underlying mechanism that contributes to pleural effusion in patients with SAPHO syndrome. Notably, pleural effusion frequently coexists with inflammation in other autoinflammatory disorders like systemic lupus erythematosus (SLE), suggesting that autoinflammation may also be an underlying mechanism. Furthermore, there have been reports that other infrequent pulmonary diseases are associated with SAPHO syndrome, including peripheral pulmonary stenosis (PPS) and lymphangioleiomyomatosis (LAM). Our study presents a case of SAPHO syndrome in a female patient exhibiting invisible organizing pneumonia, demonstrating no obvious clinical pulmonary symptoms but revealing patchy consolidation and cord shadow in the middle left lung.9 Other pulmonary manifestations included irregular linear opacities (43.3%), pulmonary opacities (32.8%), ground-glass opacities (16.4%), pleural thickening (13.4%), solitary pulmonary nodules (9%), bronchiectasis (4.5%), pulmonary bullae (3%), multiple nodules (1.5%), and reticular tumors (1.5%).10 Inflammatory bowel disease (IBD) is a chronic and recurrent inflammation of the bowel frequently associated with various immune-mediated inflammatory diseases, such as AS, rheumatoid arthritis (RA), and psoriatic arthritis (PsA).11 Also, there exists an association mechanism between SAPHO syndrome and IBD. In the study of 62 patients with SAPHO syndrome and 1309 patients with IBD, there were three patients with comorbidities. After systematic review, 39 cases of combined diseases were identified. Although the proportion of IBD patients with an association of the two syndromes is low, patients with SAPHO syndrome were not the case. Notably, SAPHO syndrome combined with IBD is more common in females, with the majority of cases complicated by Crohn's disease and primarily affecting the colon.12 However, our previous report documented four patients with IBD, including three males. Within our center's SAPHO syndrome cohort, the prevalence of IBD-associated SAPHO syndrome was found to be 0.36% (4 in 1120), predominantly occurring in the age range of 30–35.13 Several cases have documented the occurrence of IgA nephropathy in individuals with SAPHO syndrome. Morimoto et al.14 presented a case study of a 62-year-old male with SAPHO syndrome complicated by IgA nephropathy who presented with fever, sore throat, collarbone pain, and pitting edema of both lower limbs. The pathogenesis of IgA nephropathy involves the formation of IgA1 immune complexes, which play a significant role in the disease progression. Mucosal infection, especially tonsillar infection, can trigger an immune response leading to the production of B cells that generate IgA1 molecules and contribute to developing IgA nephropathy. It is noteworthy that more than approximately half of SAPHO syndrome patients have chronic tonsillitis or chronic pharyngitis.14, 15 In a previous clinical study of 58 patients with SAPHO syndrome, our team found that over 2/3 of the patients (67.2%) had tonsillitis. Follow-up of patients who underwent tonsillectomy showed improvement in bone pain and skin lesions.16 Acute anterior uveitis (AAU) demonstrates a significant correlation with the presence of HLA-B27. Spondyloarthritis associated AAU was identified in 387 (76.8%) of 504 Chinese patients with uveitis, including 214 (42.5%) with AS and 150 (29.8%) with undifferentiated spondyloarthritis-associated AAU.17 Furthermore, there exists a close relationship between SAPHO syndrome and spondyloarthritis, with the HLA-B27 gene playing a prominent role. Uveitis might be a common extra-articular manifestation of the SAPHO syndrome. Aljuhani et al.18 reported two cases of uveitis and one case of recurrent uveitis in a cohort of 41 patients diagnosed with SAPHO syndrome. Additionally, other ocular manifestations such as scleritis, retinal vasculitis, and blurred vision.19-21 Systemic autoimmune diseases have the potential to impact the nervous system, such as SLE, which can predominantly affect the central nervous system.22 In a noteworthy case, a 22-year-old male with SAPHO syndrome developed extended neurogenic muscular atrophy, with decreased strength in the hip and the knee of the left leg. Interestingly, upon resolution of the patient's clinical symptoms related to SAPHO syndrome, a reversal of the muscular atrophy was observed.23 Venous thrombosis has been observed in patients with SAPHO syndrome. Among 15 cases of venous thrombosis, 14 involved the subclavian vein, with bilateral involvement noted in five cases. The underlying mechanism responsible for venous thrombosis in SAPHO syndrome remains unclear. On the one hand, the involvement of the anterior chest wall may lead to thoracic outlet syndrome, which compresses the subclavian vein and superior vena cava, leading to chest outlet vein thrombosis. On the other hand, the autoinflammatory response affects the coagulation system, resulting in increased coagulation and increased risk of venous thrombosis.24 Osteoporosis represents a prevalent complication in rheumatic diseases. A genome-wide association study was conducted to investigate the relationship between SAPHO syndrome and abnormal osteoclast differentiation. The study enrolled 49 SAPHO syndrome patients and 121 control subjects.25 Levels of RANKL and inflammatory cytokines (including IL-1β, IL-17A, IL-6, IL-8, IL-18, and TNF-α) in patients with active SAPHO syndrome were higher than those in the healthy controls. The combined effect of increased cytokines and disrupted osteoclast differentiation pathway may aggravate bone destruction and reconstruction.26, 27 In a recent case–control study of 27 SAPHO syndrome patients and 70 healthy subjects, a higher prevalence of osteoporosis was observed among individuals with SAPHO syndrome compared to the healthy control group.28 It is plausible that bone loss in individuals with SAPHO syndrome is mediated by osteoclast activity and influenced by the underlying autoinflammatory response. Sarcopenia is the loss of muscle mass and function. It is common in young patients with autoimmune diseases, with a prevalence rate of AS ranging from 22.7% to 34.3%.29 In a study encompassing 23 SAPHO syndrome patients and 46 controls, the prevalence of fatty infiltration of muscle was significantly higher in SAPHO syndrome patients than in controls.30 A recent study reported masseter muscle involvement in patients with SAPHO syndrome.31 The precise mechanism underlying sarcopenia in SAPHO syndrome remains elusive. Chronic inflammation is a risk factor for sarcopenia, which may be related to the reason that elevated cytokine levels can reduce muscle mass and function.32 Cardiac manifestations in patients with SAPHO syndrome are rarely reported. One case of SAPHO syndrome with acute heart failure has been reported. Infection is a common cause of heart failure, and Propionibacterium acnes has been implicated in the pathogenesis of SAPHO syndrome.33 All in all, according to current research, articular and cutaneous manifestations are the primary clinical features of SAPHO syndrome. Although recent clinical discoveries have revealed the possibility of multisystemic manifestations in SAPHO syndrome, it remains elusive to determine the underlying precise mechanism of the diverse clinical manifestations of SAPHO syndrome. We postulate that there are notable similarities between SAPHO syndrome and AS. While AS is known to exhibit extra-articular manifestations, SAPHO syndrome may also present with both extra-articular and cutaneous manifestations (Table 1). All the authors participated in the conception of the work, methodology, draft preparation, edition, and final approval. None. The authors declare they have no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.