Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disease that mainly affects the metaphysis of long bones [1]. The estimated prevalence is about 1:1,000,000, with predominance in females. CRMO lacks an infectious genesis and is therefore considered to be a subtype of chronic non-bacterial osteomyelitides (CNO). Although the majority of sufferers are of juvenile or adolescent age, CRMO can also manifest in adults [2, 3]. Due to the fundamental similarities between CRMO and the SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), some authors assume them to be two clinical descriptions of the same disease pathway [4]. Simultaneous manifestations with a variety of autoimmune diseases (e. g. inflammatory bowel diseases, psoriasis or sacroiliitis) seem to be common.

Slowly developing pain combined with swelling and hyperthermia of the affected bone characterizes typical clinical findings. One key feature of CNOs is duration of symptoms for more than 6 months [5].

Specific scores and diagnostic criteria have been established to differentiate more precisely between infectious and non-bacterial osteomyelitides before initiating a treatment (Table 1; [6, 7]).

Table 1 Diagnostic criteria for non-bacterial osteomyelitides/osteitis (e. g. chronic recurrent multifocal osteomyelitis) as proposed by Jansson et al. [7]; confirmation by the presence of two major criteria or one major criteria combined with three minor criteria
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The exact pathomechanism of CRMO is still open to discussion. An imbalance between increased expression of proinflammatory cytokines (e. g. interleukins, IL, IL-1β and IL-6; and tumour necrosis factor alpha, TNF-α) and downregulation of anti-inflammatory IL-10 seems to be crucial [8, 9].

Common therapeutic approaches for CRMO include a combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids at first onset of disease, leading to response rates of about 80 % [10]. In case of insufficient remission or multiple relapses, treatment options include TNFα inhibitors, methotrexate or bisphosphonates [11]. Despite prescription of these therapeutic regimens, lasting clinical remission could only be reported in approximately 43 % of cases after a mean disease duration of 4 years [12].

The authors of this case report would like to present the potential usage of low-dose radiotherapy as a new approach for conventional treatment refractory patients.

Patient

A 67-year-old female patient with a history of chronic pain in both ankle joints was sent to the authors’ department in September 2014. Medical history revealed psoriasis vulgaris in combination with psoriatic arthritis first diagnosed in 1973. The patient reported numerous painful episodes during the past 5 years, localized particularly in the right tibia, though the pain had transformed into a constant presence 2 years ago.

In 2010, multiple arthritic bone lesions in a variety of joints of both hands and feet had been diagnosed using bone scintigraphy (Fig. 1). A dactylitis, which is specific for psoriatic arthritis, could not be shown [13, 14]. In the same year, combined immunosuppressive treatment with methotrexate and infliximab was initiated, which had remained stable since. An intensive pain therapy with hydromorphone had been escalated to 16 mg/d 1 month before first presentation to the authors’ department, but this couldn’t ease the pain.

Fig. 1
figure 1

Tc-99m Scintigraphy revealing multiple bone lesions in both hand and feet joints

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In 2014, an MRI scan of the right ankle joint depicted a massive oedema in the medullary cavity of both talus and tibia (Fig. 2). The lack of articular involvement and only small effusion in the intra-articular space were arguments against the presence of synovitis.

Fig. 2
figure 2

T2-weighted MRI scan (short tau inversion recovery, STIR, sequence) of the right ankle joint showing bone marrow oedema in the distal tibia and the talus

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At initial presentation, a pain level of 7 (during stress and resting) was measured using a visual analogue scale (VAS) ranging from 0–10. Laboratory examinations showed only moderately elevated C‑reactive protein (range between 4.7–24.3 mg/dl, standard <5 mg/dl) during the last 3 months.

Regarding the classification of Jansson et al. for CNO, three major criteria (radiologically proven bone lesion, multifocal occurrence and psoriasis) and at least three minor criteria could be established in order to justify the diagnosis of CRMO (Table 1). The diagnosis was confirmed by the experts of the local Department of Rheumatology prior to initiation of treatment.

Since both an escalated immunosuppressive therapy and the use of opioid-based drugs did not result in sufficient pain control, a low-dose radiotherapy regimen was initiated in order to modulate the excessive autoinflammatory reaction in the affected bones. Written informed consent was obtained from the patient prior to treatment.

Treatment

A planning CT scan was acquired in the treatment position using a vacuum mattress to immobilize the right leg. The planning target volume (PTV) contained the involved bone lesions of the tibia and talus with a uniform expansion of 1.5 cm. Radiotherapy was performed using 6 MV photons in a 3D conformal technique (Fig. 3). Two treatment series were applied with an interval of 6 weeks. Each series contained six fractions (three fractions per week) with single doses of 0.5 Gy, thus the total applied dose was 6 Gy.

Fig. 3
figure 3

Digitally reconstructed radiograph (DRR) of a representative therapeutic field

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Outcome

As described above, the patient initially presented with pain rating 7 on a VAS, both in a resting position and under stress. After completion of the first treatment series no improvement of symptoms could be detected. On the other hand, there was also no transient worsening of pain, which is a common acute adverse effect of x‑ray stimulation therapy of other benign bone pathologies [15, 16].

On the last day of the second treatment series there was a noticeable relief of symptoms, with a pain level of VAS 4–5 while walking and VAS 4 while resting.

The patient underwent another check-up 6 weeks after completion of the second treatment series. During this period, the positive trend towards an improvement continued. At the time of reexamination there was no determinable resting pain in the affected extremity (VAS 0). Though movement of the right foot was still painful (VAS 4), the mobility range and, consequently, the stability of the right ankle had improved in the patient’s subjective evaluation.

Another follow-up 5 months after radiotherapy demonstrated stable long-term pain control. Upon presentation at the rheumatology outpatient department 10 months after treatment, pain and symptoms of osteomyelitis had completely vanished.

It is important to mention that our local outpatient pain department did not intensify the pain medication during or after the end of radiotherapy, and treatment with immunosuppressive drugs remained stable. At the last follow-up, the hydromorphone dosage was reduced to 8 mg/d.

Discussion

Diagnosing CRMO is a challenge. Recent case studies have underlined that the preferable imaging modality for early detection of disease could be whole-body MRI, which seems to be superior to conventional radiography or Tc-99m-methyl diphosphonate (Tc-99m-MDP) scintigraphy [17, 18]. The combination of clinical findings and imaging of typical patterns of bone involvement as proposed in the score by Jansson et al. might help to avoid invasive bone biopsies in 25 % of cases [6, 12]. In this context, biopsies should only be performed in cases of unifocal bone involvement and/or if clinical findings suggest an infectious/malignant disease origin [19]. This is also due to CRMO’s unspecific histopathological appearance [20].

Treating CRMO is also challenging. NSAIDs seem to be an effective treatment at first onset of disease. A wide diversity of second-line treatments, the lack of controlled and randomized trials, and varying long-term remission rates between 22 and 48 % reflect the need for further therapeutic approaches [12]. Low-dose radiotherapy for chronically painful and degenerative bone diseases, such as arthroses or exostoses (“heel spurs”), is an established treatment procedure in Europe. Its effectiveness has been shown in a variety of studies for a wide range of indications [15, 21–24].

The German Society for Radiation Oncology (DEGRO) has released a series of practical guidelines offering consensus recommendations for radiotherapy of nonmalignant diseases [25–28].

Although appropriate treatment regimens with single doses of 0.5–1 Gy have been well known for decades, the underlying radiobiological mechanisms have just recently been revealed. Radiation-induced suppression of the functionality of peripheral blood mononuclear cells (PBMC) and migrating macrophages seems to play an important role [29].

One part of this effect relies on reduced expression of adhesion factors (e. g. E‑selectin, L‑selectin) by the vascular endothelium [30]. This lowers the overall count of PBMC able to migrate into inflammatory sites. Another important mechanism is increased production of anti-inflammatory mediators (e. g. TGF-β, IL-10) in the irradiated tissue [31]. This results in a reduced cellular activity of PBMC and macrophages.

According to a meta-analysis of different in vitro studies, the ideal single dose for maximizing these effects is within a range between 0.3 and 0.7 Gy [32].

CRMO is a painful chronic inflammatory disease, which is frequently refractory to a variety of immunosuppressive therapy regimens. Low-dose radiotherapy thus seems to be a reasonable complementary treatment.

Conclusion

To the best of the authors’ knowledge, this is the first report on the use of radiotherapy as an efficient and feasible complementary treatment for CRMO. The application of low doses per fraction is justified by the inflammatory pathomechanism of disease.