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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 13  |  Issue : 4  |  Page : 240-245

Clinical profile and treatment outcome in chronic recurrent multifocal osteomyelitis: Experience from a tertiary care center in Southern India


Department of Rheumatology, Amrita Institute of Medical Sciences, Kochi, Kerala, India

Date of Web Publication18-Nov-2018

Correspondence Address:
Sandeep Surendran
Skyline Orion 11 A, Edapally, Kochi - 682 024, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_46_18

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  Abstract 


Objective: The objective of this study was to describe clinical and radiological features and assess the treatment response in an Indian cohort of chronic recurrent multifocal osteomyelitis (CRMO).
Methods: Case records of children who were diagnosed with CRMO between January 2014 and December 2017were reviewed retrospectively. The cases were diagnosed based on the typical history along with magnetic resonance imaging (MRI). Remission was defined as resolution of symptoms along with restoration of functional status and normalization of inflammatory markers. Where available, remission was also corroborated by a repeat MRI. Clinical, radiological and treatment details were compiled.
Results: 20 children who were included, all had presented with bone pain. 10 children also has associated synovitis. The mean age at diagnosis was 11.75 years . The average period from the onset of the first CRMO symptoms to the diagnosis was 17.75 months (1–60 months) the most common bones (48%) involved the pelvic bones and femur. The mean number of lesions seen was 5.0. The initial diagnosis made were either of infection related osteomyelitis or juvenile arthritis. Nine of the 20 children had undergone bone biopsies. All 20 patients were initially started on an non-steroidal anti-inflammatory drugs (NSAIDs). Only one boy responded to just NSAIDs with all other needing second-line agents. Three patients were started on pamidronate infusions initially itself (in view of spinal involvement or difficulty in weight-bearing). A total of 15 patients were started on methotrexate as the initial second-line agent. However, four patients did not have disease control with disease-modifying anti-rheumatic drugs and later required pamidronate infusions (n = 3) and anti-tumor necrosis factor agents (n = 1).
Conclusion: In CRMO delays in referral and diagnosis may lead to prolonged courses of antibiotics, unnecessary radiation exposure from scans and unwarranted surgical procedures including repeated bone biopsies. MRI helps in early diagnosis and can avoid both unnecessary X-rays and bone biopsies.

Keywords: Chronic recurrent multi focal osteomyelitis, inflammatory osteomyelitis, non-bacterial osteitis


How to cite this article:
Surendran S, Balan S. Clinical profile and treatment outcome in chronic recurrent multifocal osteomyelitis: Experience from a tertiary care center in Southern India. Indian J Rheumatol 2018;13:240-5

How to cite this URL:
Surendran S, Balan S. Clinical profile and treatment outcome in chronic recurrent multifocal osteomyelitis: Experience from a tertiary care center in Southern India. Indian J Rheumatol [serial online] 2018 [cited 2019 Mar 24];13:240-5. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/4/240/236151




  Introduction Top


Chronic recurrent multifocal osteomyelitis (CRMO) is an idiopathic auto-inflammatory disorder affecting the bones of children. Although it is considered as a diagnosis of exclusion, a typical history should prompt an early diagnosis. Although Giedion et al. described the first case in 1972[1] as “an unusual form of multifocal chronic symmetrical osteomyelitis,” very few cases (~500) of CRMO have been reported in the literature.

Eighty-five percent of reported cases are females, with a median age of onset of 10 years.[2] The clavicular lesions are considered classical; however, the hallmark of this disease is “multifocal osteomyelitis.” Bone pain is the most common presenting symptom and children often have concomitant low-grade fever and malaise. The child can also present with arthritis secondary to reactive synovitis. The association of CRMO with palmoplantar pustulosis and psoriasis is well described. Differentiating features that suggest CRMO rather than an infective osteomyelitis include a prolonged clinical course in otherwise clinically stable child, multiple foci of osteomyelitis with associated sclerosis (chronicity), lack of fistulas, sequestra or abscess formation, lack of antibiotic response and the presence of associated inflammatory disorders such as psoriasis, palmoplantar pustulosis, or inflammatory bowel disease. Imaging is central to the diagnosis of CRMO. While plain X-rays can lytic lesions (usually in metaphysis) in the acute phase and sclerotic/mixed (lytic and sclerotic) in the chronic phase; often bone lesions are not often visible on plain X-ray.[3] Thus, the investigation of choice is magnetic resonance imaging (MRI). Characteristic findings include well-circumscribed metaphyseal lesions T1 hypo-intense and T2 hyper-intense lesions along with short tau inversion recovery (STIR) sequences showing focal hyperintensities secondary to bone marrow edema. Non-metaphyseal lesions and periosteal thickening maybe also be seen on MR.[3],[4] Tc-99 whole body bone scintigraphy is another modality that can demonstrate multifocal bone inflammation. Histopathology of the bone lesions just shows nonspecific findings consistent with inflammation is often done to rule out other etiologies.

Evidence about the Indian experience is very limited. Patients often present to rheumatology clinics after being treated by orthopaedic surgeons as infective osteomyelitis for prolonged courses of antibiotics along with unnecessary repeated biopsies and surgical debridement of the lesions.


  Methods Top


Case records of all the children (aged < 18 years) who were diagnosed as CRMO between January 2014 and December 2017 at our institute were analysed. CRMO was diagnosed based on the symptoms (bone pain +/- synovitis) along with MRI scanning showing the typical findings of CRMO. Remission was defined as resolution of symptoms along with restoration of functional status and normalization of inflammatory markers. If available, remission was corroborated by repeat MRI.

The details of the patients collected were as follows – age of child, sex, time from symptom onset to diagnosis, initial diagnosis, psoriasis or family history of psoriasis, bone biopsy and number of prior surgeries. The distribution and location of bone lesions and synovitis in each CRMO patient was also collected. The presence of other associated diseases like inflammatory bowel disease along with the duration of follow-up was also noted.

All children were treated NSAIDs, DMARDs and/or bisphosphonates as per protocol. The details of protocol are mentioned in the discussion. The clinical, biochemical and radiological (if available) response to treatment was collected.

Statistical analyses

All results were compiled on Microsoft Excel 2014. Continuous variables (eg, age, duration to diagnosis) summarised using mean and median. Categorical variables (e.g., gender) were summarised using proportion and percentage.

Ethical approval

The study protocol and other relevant documents for this study were reviewed by the Institutional Ethic Committee (IEC) and ethical clearance was given by the IEC for compiling this review.


  Results Top


Twenty children diagnosed as CRMO at our institute from January 2014 to December 2017 were included. One child diagnosed with CRMO in our cohort was from Maldives, but all others were Indians. All 20 cases had presented with bone pain while 10 children also had associated arthritis. The summary of the case details of our cohort is shown in [Table 1] which shows the demographics, time to diagnosis, the initial referring diagnosis, psoriasis, or family history (1st degree) of the same, number of prior surgeries, number of lesions along with the distribution of lesions and synovitis. Only one child had an associated inflammatory bowel disease. Totally, there were 100 lesions. All bone biopsy (n = 9) predominantly showed nonspecific and nongranulomatous inflammation. Of these, 5 were further operated by orthopaedic surgeons as cases of osteomyelitis. In fact, 2 children (10% of total CRMO) underwent multiple surgeries for diagnostic purposes. Overall 8 children had received prolonged (>4 weeks of antibiotics) suspecting an infectious etiology. In fact, 2 children had been even given anti tubercular therapy (ATT) also.
Table 1: Clinical features of our cohort

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MRI confirmed the diagnosis in all 20 children showing multiple T1 hypo-intense and T2 fat-suppressed lesions along with STIR showing bone marrow edema in all except one. Example of this is shown in [Figure 1]. [Table 2] summarizes the biochemical and radiological findings of our cohort.
Figure 1: T2FS hyperintense signals involving bilateral sacroiliac joint (R>L) right inferior pubic ramus and bilateral neck of the femur (black arrow) Postcontrast enhancement noted involving the medial aspect of the right metaphysis of tibia extending into the growth plate and the epiphysis (white arrow)

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Table 2: The biochemical and radiological features of our cohort

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All 20 patients were initially started on an non-steroidal anti-inflammatory drug NSAID (naproxen 20 mg/kg/day). Only one boy responded to just the NSAID (who interestingly had only vertebral lesions) with all other cases needing second-line agents. One girl diagnosed in December 2017 (case no 20) and started on treatment with NSAIDs. Her clinical response on NSAIDs is awaited at the time of submission. Three patients were started on pamidronate infusions upfront itself (1 in view of spinal involvement and 2 as they had difficulty in weight bearing). They were started on weekly methotrexate (MTX) also after six monthly infusions were completed. The remaining 15 patients who showed excellent response to NSAIDs were added on MTX (10 mg/m2). In addition, five patients were also added on sulfasalazine initially. While 11 patients had good clinical response with this combination of NSAIDs and MTX with or without sulfasalazine, four patients did not have disease control (all four having symptoms with high inflammatory markers with 1 child showing active lesions on MR). Three of these patients were started on pamidronate infusions in addition to the disease-modifying antirheumatic drugs (DMARDs). The other child in view of co-existent psoriatic nail changes was started on an anti-tumor necrosis factor (TNF) agent instead of pamidronate and showed good response. The other 11 patients were slowly stopped on NSAIDs and continued on the DMARDs only. [Table 3] shows the treatment details of the individual patients along with radiological response if available for the respective cases. Follow-up scans are available for 5 of these 11 patients who had the combinations of NSAIDs with MTX only as the second-line agent and show good radiological involvement. Of the total six patients who have got pamidronate, 4 children have follow-up scans showing radiological involvement corroborating the clinical and biochemical improvement. The median follow-up of the patients in our cohorts is 11.5 months (range = 1 month to 3.75 years). Seven of the 20 children in our cohort were lost to our follow-up after symptomatic and biochemical improvement from the initial presentation. Three of these children had repeat imaging showing improvement before they were lost to follow-up. None of these patients had received pamidronate. One child had presented in remission while on MTX and was asked to continue follow-up with his primary treating rheumatologist after 3 months.
Table 3: The treatment details of individual patients and their response

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  Discussion Top


CRMO is an entity which clinicians need to be aware of; as all bone inflammation is not infection. This lack of awareness was evident in our cohort as 20% of children (2 of 20) of our cohort underwent multiple unnecessary procedures. [Table 4] shows a comparison of our cohort with UK and Australian cohorts of CRMO as reported by Roderick et al.[2] and Walsh et al.[5] the heterogeneity of the clinical presentations between populations can be seen. Of note is the lower incidence of the classical clavicular involvement and vertebra involvement in our cohort as compared to the other cohorts. Instead, our patients have marked lower limb predominance of the lesions with 58% of the lesions occurring in pelvis, femur, tibia, and fibula along with higher incidences of psoriasis and arthritis symptoms (especially when comparing with the UK cohort). As this is a retrospective study, there are some limitations in the data collected. Although given cost constraints, MRI was done only for the symptomatic regions in our cohort, the mean lesions are higher in our cohort when compared with the other cohorts. In addition, follow-up whole-body MRI has described in published was not done due to the exorbitant cost. As CRMO is well known to have silent and quiescent lesions, some lesions might have been missed and the actual number of lesions are probably higher in Indian patients.
Table 4: Comparison of our data with other chronic recurrent multifocal osteomyelitis cohorts

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There are no clear-cut protocols in the treatment of CRMO. Most of the treatment recommendations and available experience are from a few prospective studies, case series, and reports. The largest cohort which proposes a treatment guideline is from 2015 by Roderick et al.[2] Our experience is from 2014 onward. Our treatment protocol is as follows:

  • In consideration with available evidence all patients have been considered for NSAIDs.
  • The patients with significant spinal involvement or having lesions affecting daily functioning were considered for pamidronate at the onset. Those who become symptomatic on weaning naproxen or had inadequate symptomatic relief to naproxen and DMARDs were considered for pamidronate also.
  • DMARDs (MTX + sulfasalazine) were given in addition to NSAIDs if the child had good response to NSAIDs and the presence of other co-variables (psoriasis and associated synovitis). NSAIDs were slowly tapered off and the child was continued on DMARDs. Children who experienced a flare on this regimen were considered for pamidronate.


On reviewing the available literature, the first-line treatment that has been extensively described is NSAIDs. The efficacy of NSAIDs has been well studied in a prospective study by Beck et al. in German children in 2011.[6] They demonstrated a good response with 43% of children asymptomatic on naproxen (15 mg/kg/day) at 6 months and reduction of the bone lesions from 183 to 81 with treatment. Although those with peripheral arthritis and spinal involvement did not respond adequately in their study. Interesting, the only patient in our cohort who responded to NSAID alone, had predominantly spinal lesions.

Several agents have been utilized for failure or partial response to NSAIDs, including MTX, sulfasalazine, pamidronate, and anti-TNF agents. Almost all our patients were given a second-line agent to control the disease. Most of the reported literature for second-line therapy consists of case reports and series. In our case series, unless there is spinal involvement, the second-line agent used was weekly MTX (10 mg/m 2). The evidence for usage of MTX is limited to retrospective case analyses as shown Borzutzky et al.[7] along with expert consensus.[8] We had 15 patients given combination of MTX with NSAIDs responded to treatment, and 9 responded clinical and biochemically. 4 of these 9 children also have repeat MRI documenting the same. Two patients have been recently started on MTX and have shown symptomatic improvement. Their repeat inflammatory markers and imaging are due in the follow-up visits. However, the remaining four patients who got MTX in combination with NSAIDs did not respond. They were give pamidronate (n = 3) and anti TNF therapy (n = 1).

There is much more evidence for this usage of pamidronate in CRMO. Miettunen et al.[9] conducted a prospective analysis of the response to bisphosphonates and treated nine patients with pamidronate. In addition, Hospach et al.[10] have retrospectively reviewed the use of pamidronate in patients with spinal involvement and showed relief of pain in seven patients within 3 months with partial or complete resolution of vertebral hyperintensities on MRI after 13 months. In our cohort, totally 6 patients have received pamidronate of which 3 were refractory to DMARDs, and all six patients showed a good response to treatment. Coming to the usage of biologics for CRMO especially anti-TNF agents have been well described. Twilt et al. showed a good response in 6 patients who were treated with infliximab.[8] The one boy in whom we used anti-TNF therapy was refractory to oral DMARDs and had co-existent psoriatic lesions. He had good response with the same.

In summary, CRMO should be considered in children with multifocal bone inflammation (osteomyelitis). Our Indian data shows lower limb predominance of the lesions with lesser frequencies of “classical” clavicle and vertebral involvement. Psoriasis or family history of psoriasis is a key clinical feature. MRI is the best diagnostic modality for demonstrating the multi-focal bone inflammation with no sequestrum or significant abscess formation; unlike in infective osteomyelitis. The first line therapy is NSAIDs, but most patients needed a second line agent. Pamidronate is, however, the drug choice especially for CRMO with spinal involvement or refractory cases with oral DMARDs alone. Our study reports 73% response to NSAIDs plus MTX, which allowed tapering of NSAIDs and maintenance of clinical remission with weekly MTX. The safety for long-term usage of MTX and affordability is well known. Bisphosphonate therapy also showed good efficacy, and its lower cost (when compared to biologic therapy) and lack of immunosuppression profile make it an appealing agent. However, caution is necessary as there are safety questions regarding continuation of long term bisphosphonates in young girls. The optimal treatment strategy for CRMO is still unknown as there are no RCTs yet available; however, use of low dose MTX in patients who had good response to NSAIDs maybe a cost-effective and prudent strategy.


  Acknowledgments Top


We would like to thank Dr. Vinod Krishnan from the Department of Orthopaedics at AIMS, Kochi, for his help in building our cohort. We would also like to thank the Department of Radiology for their assistance with imaging our patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Giedion A, Holthusen W, Masel LF, Vischer D. Subacute and chronic “symmetrical” osteomyelitis. Ann Radiol (Paris) 1972;15:329-42.  Back to cited text no. 1
    
2.
Roderick MR, Shah R, Rogers V, Finn A, Ramanan AV. Chronic recurrent multifocal osteomyelitis (CRMO) – Advancing the diagnosis. Pediatr Rheumatol Online J 2016;14:47.  Back to cited text no. 2
    
3.
Surendra G, Shetty U. Chronic recurrent multifocal osteomyelitis: A rare entity. J Med Imaging Radiat Oncol 2015;59:436-44.  Back to cited text no. 3
    
4.
Khanna G, Sato TS, Ferguson P. Imaging of chronic recurrent multifocal osteomyelitis. Radiographics 2009;29:1159-77.  Back to cited text no. 4
    
5.
Walsh P, Manners PJ, Vercoe J, Burgner D, Murray KJ. Chronic recurrent multifocal osteomyelitis in children: Nine years' experience at a statewide tertiary paediatric rheumatology referral centre. Rheumatology (Oxford) 2015;54:1688-91.  Back to cited text no. 5
    
6.
Beck C, Morbach H, Beer M, Stenzel M, Tappe D, Gattenlöhner S, et al. Chronic nonbacterial osteomyelitis in childhood: Prospective follow-up during the first year of anti-inflammatory treatment. Arthritis Res Ther 2010;12:R74.  Back to cited text no. 6
    
7.
Borzutzky A, Stern S, Reiff A, Zurakowski D, Steinberg E, Dedeoglu F, et al. Pediatric Chronic Nonbacterial Osteomyelitis. PEDIATRICS 2012;130:e1190-7.  Back to cited text no. 7
    
8.
Twilt M, Laxer RM. Clinical care of children with sterile bone inflammation. Curr Opin Rheumatol 2011;23:424-31.  Back to cited text no. 8
    
9.
Miettunen PM, Wei X, Kaura D, Reslan WA, Aguirre AN, Kellner JD, et al. Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J 2009;7:2.  Back to cited text no. 9
    
10.
Hospach T, Langendoerfer M, von Kalle T, Maier J, Dannecker GE. Spinal involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate. Eur J Pediatr 2010;169:1105-11.  Back to cited text no. 10
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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