Garre’s sclerosing osteomyelitis also known as chronic non-suppurative sclerosing osteomyelitis is a specific type of osteomyelitis that particularly affects children and adolescents [1]. It has been reported in association with several chronic autoimmune diseases, including inflammatory bowel disease, granulomatosis with polyangiitis, psoriasis, and Takayasu arteritis [2]. It affects principally the mandible [3], but it can occur in any bone [2] and it generally originates from a low virulence infection [1].

Infectious complications that increase morbi-mortality in patients with systemic lupus erythematosus (SLE) are frequent and well-recognized. Goldblatt et al. reported 25.4 % of deaths due to infection [4]. SLE is a frequent underlying condition of bacteremia by salmonella [5]. Extra-intestinal focal infections caused by salmonella described in SLE are pneumonia, meningitis, urinary tract infections, pericarditis, skin abscesses, septic arthritis, and—as in our case—osteomyelitis [6].

Despite being associated with autoimmune diseases, Garre’s sclerosing osteomyelitis is a rare entity with only a few cases related to SLE published in the literature this far. A recent observation in our institution prompted this report.

Case report

We report the case of a 35-year-old male who early in 2010 and within the span of about a month was diagnosed with APS and SLE. Early in January, he presented with an acute pulmonary embolism (PE) with anti-cardiolipin and anti-beta-2 glycoprotein positivity and in February with joint (knee synovitis), serosal (pleural effusion), hematological (lymphopenia), and renal involvement (24-h proteinuria 1328 mg/dl, a kidney biopsy showing Class II lupus nephritis) with positive ANA (1:640—homogenous pattern), anti-dsDNA and anti-histone antibodies. He was put on warfarin and high dose prednisone with gradual tapering to 10 mg. In May 2010, hydroxychloroquine and methotrexate were added to the therapeutic regimen. Azathioprine 150 mg/day was started instead of methotrexate and later stopped in 2012 based on elevated serum transaminases; subsequently cyclosporine 50 mg/day was started, and gradually increased to 150 mg/day. In March 2013, the patient was receiving prednisone 10 mg/day, hydroxychloroquine 200 mg/day, methotrexate 12.5 mg/week, leflunomide 20 mg/day, and oral anticoagulation.

In March 2014, the patient presented to our emergency room with a 1-week history of claudication and severe pain in his left thigh exacerbated by palpation and physical activity, malaise, and fever (39 °C). White blood cell count (WBC) was 6000/mm3 (absolute neutrophil count (ANC) 4800, absolute lymphocyte count (ALC) 720 and absolute monocyte count (AMC) 72, C-reactive protein (CRP): 58.2 mg/L (Reference range, <1 mg/L), and erythrocyte sedimentation rate (ESR): 34 mm/h). An antero-posterior X-ray film of the left femur showed cortical thickening and periosteal reaction along the diaphysis (Fig. 1). Empirical initial therapy with vancomycin for three weeks was started on March 6th; the patient had a torpid hospital stay with persistent fever and pain in his left thigh, leucocytosis with neutrophilia and left shift. Scintigraphy revealed increased flow and tracer uptake—in the middle and distal third of the left thigh soft tissues; the delayed phase showed increased uptake in the same area. Additionally, a multi-slice helical computed tomography (CT) showed increased density of the intramedullary bone, endosteal reaction, and narrowing of the medullary cavity in the left femur (Fig. 2).

Fig. 1
figure 1

Lower limb X-ray film showing cortical thickening and periosteal reaction of the diaphysis of the left femur

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Fig. 2
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Non-contrast axial computarized tomography (CT) through the proximal thighs showing increased density of the intramedullary bone, endosteal reaction, and narrowing of the medullary cavity of the left femur

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Subsequently a magnetic resonance imaging (MRI) of both thighs was performed and showed hypodensity on T1-weighted images from the distal femoral diaphysis to the epiphysis, significant multilayered periosteal reaction in the middle and distal third of the diaphyseal cortex, and irregular endosteal border with hyposignal (Fig. 3); the STIR images showed periosteal reaction and soft tissue edema (Fig. 4).

Fig. 3
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Coronal MRI of thighs showing hypodensity on T1-weighted images from the distal femoral diaphysis to the epiphysis, significant multilayered periosteal reaction in the middle and distal third of the diaphysis cortical, and irregular endosteal border with hyposignal in the left femur

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Fig. 4
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MRI showing on STIR images periosteal reaction and soft tissue edema in the left femur

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Three weeks after initiation of vancomycin, a surgical bone biopsy was performed and showed osteoblastic activity in the cortical tissue and mixed inflammatory infiltrate in the stroma; in the medullary tissue, changes suggestive of chronic and acute osteomyelitis were found with devitalized tissue and apposition of new bone.

Salmonella spp. Group D Vi negative was isolated from the medullary cavity. The patient was then treated with ceftazidime and cotrimoxazole for 4 weeks; subsequently doxycycline and cotrimoxazole were prescribed for four additional months with the patient experiencing a full recovery.

Discussion

Sclerosing osteomyelitis is a specific type of chronic osteomyelitis described by Carl Garre in 1893 [1] as a focal gross thickening of periosteum with peripheral reactive bone formation resulting from infection, henceforth Garre’s sclerosing osteomyelitis [7]. This entity is seen in children, adolescents, and young adults [8]. In young people, the persistence of considerable activity of osteoblastic cells in the periosteum is responsible for causing a condensation of cortical bone rather than an osteolytic process. It usually affects the mandible [1], but it has been reported in several bones like femur, tibia, humerus, and others [9].

Osteomyelitis in SLE is unusual; however, it should be noted that salmonella, an uncommon pathogen for osteomyelitis in normal hosts, has repeatedly been reported to be a causative agent in these patients [10]. In their report Lim et al. remarked that most salmonella infections occur during periods of active SLE (83 % SLEDAI ≥ 4), and that the mainly serogroups isolated were B and D [6]. Wu et al. reported coexistent underlying systemic disease, chronic renal disease, and intensive immunosuppressive therapy as predisposing factors for osteomyelitis [10]. Furthermore, Salmonella bacteremia is commonly associated with SLE [5]; for example, in a survey of patients with gram-negative bacteremia conducted in a New York hospital 30 were due to salmonella species, lupus patients accounted for 6 out of these 30 cases, but only for 13 out of 2388 non-salmonella gram-negative bacteremias, suggesting that SLE patients are at increased risk for salmonella sepsis [11].

In general, severe infections contribute to morbidity and mortality of SLE patients. Around 50 % of SLE patients will have one or more events during their lifetime [12] and will be responsible for approximately 25 % of all deaths [13]. For example, in the GLADEL cohort, the largest Latin-American lupus cohort, infections were the first cause of death [14]. Risk factors for infection are disease activity, associated comorbidities, the use glucocorticoids with doses over 7.5 mg/day [5], and genetic factors like complement deficiencies—lower concentrations of C3—[12], allelic variants of Fc gamma receptor—like Fc gamma RIIA-H131 that also increased the risk for lupus nephritis—[15], and amplified expression of colony-stimulating factor-1 (CSF-1) which also correlated with the onset and recurrence of lupus nephritis [16]. Additionally, the presence of the silent polymorphism at position 707 (707C > T) (rs1126616) in the case of osteopontin is associated with opportunistic infections [17] and the mannose-binding lectin 2 (MBL2) O/O genotype with an increased incidence of gram-positive infections [18]. Lymphopenia is also a strong predictor factor for infections in SLE [19].

In short, patients with SLE have a higher risk of infection than the general population and—in some studies, salmonella has been the most frequently isolated gram-negative organism recovered from their blood. Salmonella osteomyelitis is not unusual in SLE patients, but Garre’s sclerosing osteomyelitis certainly is. It is important to exclude infections in SLE patients, because they can masquerade as exacerbation of the disease and if they go undetected could contribute to significant morbidity and early mortality in these patients.