Azithromycin: Eine anti-inflammatorische Wirksamkeit im Einsatz bei der chronischen rekurrierenden multifokalen Osteomyelitis? Eine vorläufige Mitteilung

In this preliminary communication we report our experience with Azithromycin in patients with Chronic Recurring Multifocal Osteomyelitis (CRMO). Seven out of 13 patients, mainly teenager, showed a fast clinical improvement after they were started on Azithromycin. The immediate therapeutic effect of Azithromycin in patients with CRMO was surprising and lead us to the hypothesis that Azithromycin could have an antiphlogistic in addition to it's antibiotic effect in this disease setting. In patients with reactive chronic pelvic osteomyelitis Azithromycin obviously had a direct influence on the sympathic coxitis. Half of the patients reported an immediate reduction of pain and a significant improvement in range of movement after they were started on Azithromycin. In all cases the clinical and radiographic signs on MRI showed a reduction of the inflammatory process. Experimental animal models have recently shown that macrolids have independent additional antiinflammatory and immunomodulatory effects. The assumed local immunomodulatory effect of Azithromycin potentially is an additional activity to the already known synergistic antimicrobial and antiinflammatory effect. Right now we are in the process of collecting data from patients with SAPHO Syndrome who underwent bone-biopsies for microbiologic and histomorphologic investigations. All patients with the growth of propionibacterium acnes were started on a long-term antibiotic therapy with Azithromycin. This study will possibly help to answer the question of the additional antiphogistic/immunomodulatory effect of Azithromycin in this disease entity and the related CRMO.     

Childhood chronic recurrent multifocal osteomyelitis: pamidronate therapy decreases pain and improves vertebral shape

OBJECTIVE: Chronic relapsing multifocal osteomyelitis (CRMO) results in significant morbidity, especially in those with vertebral collapse. Symptomatic benefit with intravenous pamidronate (PAM) has been shown; however, few studies have demonstrated radiological benefit. We describe clinical and radiological data on 7 pediatric cases of CRMO treated with PAM. METHODS: Retrospective chart review on all children with CRMO treated with PAM. Response to PAM was measured by subjective reports and radiology including vertebral morphometry. RESULTS: Seven patients (1 male) presented with bone pain at a median age of 8 years (range 5-14). Symptoms had been present for a median of 18 months (range 11-51) before PAM therapy. All patients had involvement of multiple nonspinal sites, 5 children had spinal involvement with vertebral fractures, and 5 had joint involvement. Six cases had symptomatic improvement within 6 months of starting PAM, which was sustained during PAM therapy (median 26 mo, range 6-41) and persisted in the 4 cases who had ceased treatment for the duration of followup (27 mo, range 18-51). The least benefit was seen in the 3 cases with synovial joint involvement. The 3 cases with spinal radiological followup showed modeling of vertebral fractures and in one patient improvement in kyphosis. No radiological improvement in nonspinal lesions was seen. CONCLUSION: PAM therapy was associated with symptomatic improvement and vertebral modeling in children with CRMO. We suggest that children with bone pain and/or spinal involvement be considered for PAM therapy early after diagnosis.     

Osteonecrosis of the jaw associated with pamidronate therapy

Bisphosphonates are commonly used in the treatment and prevention of osteoporosis, and they are also an important therapeutic adjunct in multiple myeloma and other cancers metastatic to bone. Bisphosphonates are generally well tolerated and associated with minimal adverse effects; however, there exists a growing concern that intravenous bisphosphonate use is associated with osteonecrosis of the jaw (ONJ). We report the occurrence of osteonecrosis of the jaw associated with pamidronate therapy in 12 patients diagnosed with multiple myeloma, breast carcinoma, or renal cell carcinoma, all involving bone. At the onset of jaw osteonecrosis, pamidronate therapy was the single medication common to all 12 patients. The duration of therapy varied from 12 to 77 months before osteonecrosis was observed; 92% (11/12) of cases involved the posterior mandible and all cases have been refractory to a variety of medical therapies, including surgical debridement and systemic antibiotics. Available tissue biopsies revealed inflammation consistent with osteomyelitis. In one biopsy, Actinomyces spp. were recovered from culture, but treatment with an extended course of clindamycin conferred no clinical benefit. The persistence of exposed bone remains a significant source of morbidity and pain for each surviving patient. Discontinuation of pamidronate therapy has not helped reverse the presence of osteonecrosis, and surgical manipulation of the involved site appears to worsen the underlying bone pathology. ONJ is an important adverse outcome associated with bisphosphonate therapy, and physicians prescribing pamidronate or zoledronate must be aware of the association between these drugs and this serious clinical entity. Failure to recognize the signs of ONJ can lead to unnecessary surgical procedures, which ultimately exacerbate the condition and impact quality of life. The unremitting nature of this clinical development, and the long-lasting morbidity associated with it suggests that patients should be counseled regarding the possible occurrence of ONJ prior to initiating therapy with pamidronate.     

Sternocostal involvement in chronic recurrent multifocal osteomyelitis associated with ulcerative colitis

Chronic recurrent multifocal osteomyelitis (CRMO) is a chronic, relapsing, inflammatory, non-infectious disorder of the skeletal system and is of unknown origin. Early diagnosis of the disease is essential to exact treatment. The relationship between inflammatory bowel disease and CRMO is understood as extraintestinal rheumatic manifestations. CRMO associated with ulcerative colitis (UC) is very rarely reported. This case is first report of sternocostal involvement in CRMO associated with UC.     

Chronic non-bacterial osteomyelitis in children

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) in children is a chronic non-suppurative inflammation involving multiple sites. Some children affected by chronic non-bacterial osteomyelitis (CNO) do not have multiple lesions or a recurrent course. OBJECTIVE: To characterise the long term outcome of children with the full spectrum of CNO. METHODS: 30 children diagnosed with CNO were followed up for a mean of 5.6 years and their disease assessed using a clinical score, multiple imaging, and a diagnostic biopsy, including extensive microbial analysis. RESULTS: 9 patients had unifocal non-relapsing disease, 3 unifocal lesions with relapses, 9 multifocal lesions without relapses, and 9 multifocal lesions with relapses (CRMO). Granulocytes were present significantly more often in CRMO than in unifocal and non-recurrent lesions. Pustulosis was more common in multifocal cases regardless of recurrence. Mean duration of treatment in 15 children with a single occurrence was 9.2 months. Naproxen treatment was generally effective. Naproxen treatment in 12 patients with relapses lasted 25 months. However, 7 of these were not effectively treated with naproxen alone. Five were treated with oral glucocorticoids for 27 days in addition to naproxen, which induced remission in four, lasting for at least 1.5 years. Longitudinal growth of affected bones was not altered, except for the development of hyperostosis. CONCLUSION: CNO is a spectrum of inflammatory conditions, with CRMO being the most severe. Most children with CNO have a favourable outcome of the disease. Oral glucocorticoids may be necessary in severe recurrent cases.     

An unusual presentation of chronic recurrent multifocal osteomyelitis involving bones of the skull

Chronic recurrent multifocal osteomyelitis is a rare, multisystemic inflammatory disease that affects children and adolescents. We present the case of an African-American adolescent male who presented with recurrent swelling of the temporal region with skull involvement on head imaging, which is atypical for chronic recurrent multifocal osteomyelitis. He had clinical and laboratory improvement after initiation of indomethacin and pamidronate.     

Current Understanding of the Pathogenesis and Management of Chronic Recurrent Multifocal Osteomyelitis

Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder that primarily affects children. Its hallmark is recurring episodes of sterile osteomyelitis. The clinical presentation is insidious onset of bone pain with or without fever. Laboratory studies typically reveal nonspecific evidence of inflammation. Radiologic imaging and histologic appearance resemble those of infectious osteomyelitis. There is a strong association with inflammatory disorders of the skin and intestinal tract in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic component to disease susceptibility. Two genetic syndromes have CRMO as a prominent phenotype—Majeed syndrome and deficiency of the interleukin-1 receptor antagonist—and suggest that interleukin-1 may be a key cytokine in disease pathogenesis. This review briefly summarizes the main clinical and radiologic aspects of the disease and then focuses on genetics and pathophysiology and provides an update on treatment.     

Das SAPHO-Syndrom: Klinisch-rheumatologische und radiologische Differenzierung und Klassifizierung eines Krankengutes von 86 Fällen

Synovitis (inflammatory arthritis), acne (pustulosa), pustulosis (psoriasis, palmoplantar pustulosis), hyperostosis (acquired), and ostitis (bland osteomyelitis) are symptoms forming the acronym SAPHO, which is a syndrome of nosologic heterogeneity. All entities forming the SAPHO syndrome are connected by a non-obligate dermatoskeletal association with an aseptic pustulous character. 86 cases were analyzed clinically, radiologically and by histology/histopathology. 31 adult patients showed the typical triad of pustulosis palmo-plantaris (psoriatica, PPP), sterno-costo-clavicular hyperostosis (SCCH), and "productive" spondylopathy, which we define as entity I. spondarthritis hyperostotica pustulopsoriatica (Spond.hyp.pp). Twelve adolescent and 13 adult patients showed entity no. II: chronic recurrent multifocal osteomyelitis (CRMO), being characterized by non-purulent osteomyelitis of plasma-cell sclerotic type, potentially being a reactive inflammatory process. 50% of the adult patients with CRMO showed PPP. Differentiation between these two entities is possible by detection of ossifying enthesiopathy in cases of Spond. hyp.pp and primarily chronic osteomyelitis in cases of CRMO. Two more entities or abortive forms of group I and II are III: the inflammatory syndrome of the anterior chest-wall (ACW syndrome) and IV: the more productive form of isolated sterno-costoclavicular hyperostosis (SCCH). Both are connected quite frequently to HLA-B-27-independent forms of spondarthritis and to pustulous dermatosis. More rarely we find osteo-articular symptoms in cases of acne pustulosa, which form group V: acne-associated spondarthritis and CRMO in the case of acne. Adult forms of CRMO with different forms of appearance (lumosacro-iliac hyperostosis with retroperitobeal fibrosis, pelvic type with affection of the hip-joint) are described. The immunologic theory of a "reactive osteomyelitis" potentially triggered by saprophytes is described. The inverse acne triad is brought in a context of skin symptoms. A case of intercurrent postpartum symptoms together with ulcerative colitis is described. Three cases of patients with Crohn's disease are described. Clinical features, radiological findings, and histopathological elements are brought together to determine the connections between the different entities and the possibilities of differentiation. With these elements together with bone-scan, it is often not necessary to obtain a bone specimen. Therapeutical possibilities, especially concerning CRMO, are discussed. "SAPHO syndrome" is more a sign-post on the way to a more subtle diagnosis when it comes to hyperostotic, skin-associated diseases, and it needs interdisciplinary work to clear the situation.     

Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO)

Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn’s disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal–Wallis and Mann–Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn’s disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn’s disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn’s disease patients with “bone pain” and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.     

The Dilemma of Chronic Recurrent Multifocal Osteomyelitis

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare idiopathic inflammatory disease that affects mainly children and young adults, resulting in significant morbidity especially if not diagnosed early. The clinical signs and symptoms are nonspecific, with a consequential delay in diagnosis. Radiological and histopathological criteria are important for its definition. Two cases of CRMO are reported, highlighting the diagnostic challenge and demonstrating the importance of timely investigations.     

Chronic Recurrent Multifocal Osteomyelitis Associated with Chronic Inflammatory Bowel Disease in Children

Chronic recurrent multifocal osteomyelitis(CRMO) is a rare disease of children characterized byaseptic inflammation of the long bones and clavicles. Noinfectious etiology has been identified, and CRMO has been associated with a number of autoimmunediseases (including Wegener's granulomatosis andpsoriasis). The relationship between CRMO andinflammatory bowel disease is poorly described. Throughan internet bulletin board subscribed to by 500pediatric gastroenterologists, we identified sixinflammatory bowel disease patients (two with ulcerativecolitis, four with Crohn's colitis) with confirmed CRMO. In all cases, onset of the bony lesionspreceded the onset of bowel symptoms by as much as fiveyears. Immunosuppressive therapy for the bowel diseasegenerally resulted in improvement of the bone inflammation. Chronic recurrrent multifocalosteomyelitis should be considered in any inflammatorybowel disease patient with unexplained bone pain orareas of uptake on bone scan. CRMO may be a rareextraintestinal manifestation of inflammatory bowel disease;alternatively, certain individuals may be geneticallypredisposed to the development of bothdiseases.     

Long-term intravenous antibiotic therapy in chronic osteomyelitis

Because the optimal treatment of chronic osteomyelitis is not well established, we studied the efficacy of prolonged (three months or more) outpatient intravenous antibiotic therapy via a Hickman catheter. Seventeen patients were entered into our protocol (13 with chronic osteomyelitis, three with chronic septic arthritis, and one with subacute osteomyelitis). Pseudomonas aeruginosa was the most common bone isolate, followed by Staphylococcus aureus. Most patients had polymicrobial isolates. Patients were followed up with clinical examinations, serial measurements of erythrocyte sedimentation rate, and scans using technetium Tc 99m medronate and gallium citrate Ga 67. Of the ten patients with chronic osteomyelitis who completed therapy, eight were considered cured. After further follow-up, three of the cured patients had recurrences requiring additional therapy.     

Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone

Intravenous infusions with the bisphosphonate compound pamidronate decrease bone pain and reportedly can lead to refilling of dysplastic lesions in adults with fibrous dysplasia (FD) of bone. Here we describe the effects of this treatment approach in 18 children and adolescents (age at start of therapy, 6.2-17.5 yr; eight girls) with polyostotic FD, who received pamidronate for 1.2-9.1 yr (median, 3.8 yr). Treatment cycles with pamidronate (1-1.5 mg/kg.d on 3 consecutive days) were given every 4 months. Levels of serum alkaline phosphatase and urinary collagen type I N-telopeptide were elevated at baseline and decreased continuously during the first 3 yr of therapy. There was no radiographic evidence of filling of lytic lesions or thickening of the bone cortex surrounding the lesions in any patient. Histomorphometric results in dysplastic bone tissue of patients receiving pamidronate (n = 7; time of therapy, 1.4-4.8 yr) were similar to those of patients without medical therapy (n = 9). No serious side effects were noted. In conclusion, pamidronate therapy appears to be safe in children and adolescents with polyostotic FD. However, we found no clear evidence that pamidronate has an effect on dysplastic lesions in such patients.     

Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions

Objective

To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies.

Methods

Virtual and face‐to‐face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions.

Results

Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response.

Conclusion

Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.

     

Tumor necrosis factor alpha-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin

OBJECTIVE: To study the effects of osteoclast-targeted therapies, such as osteoprotegerin (OPG) and pamidronate, on joint inflammation and bone destruction using a tumor necrosis factor alpha (TNF alpha)-transgenic mouse model. METHODS: Mice were placed into 5 groups that received either OPG, pamidronate, a combination of both agents, infliximab as a positive control, or phosphate buffered saline as a negative control. Treatment was initiated at the onset of arthritis, continued over 6 weeks, and thereafter, the clinical, radiologic, and histologic outcomes were assessed. RESULTS: A significant improvement in clinical symptoms, as assessed by the reduction of paw swelling, was only found in the infliximab group, whereas all other treatment groups failed to show significant improvement. However, when assessing structural damage with radiographic analysis, a significant retardation of joint damage was evident in animals treated with OPG (55% reduction of erosions), pamidronate (50% reduction of erosions) the combination therapy of OPG and pamidronate (64% reduction of erosions), and with infliximab (66% reduction of erosions). Confirming these data, quantitative histologic analysis revealed a significant reduction in the size of bone erosions in all treatment groups (OPG 56%, pamidronate 53%, OPG and pamidronate 81%, and infliximab 46%) compared with the control group. Furthermore, a significant reduction of osteoclast numbers was seen in animals treated with OPG alone or in combination with pamidronate as well as in animals treated with infliximab. CONCLUSION: These data suggest that OPG alone or in combination with bisphosphonates is an effective therapeutic tool for the prevention of TNF alpha-mediated destruction of bone by reducing the number of bone-resorbing cells in the inflammatory tissue.     

The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment

Mucolipidosis type III (ML III; McKusick 252600) is a rare lysosomal storage disease in which skeletal involvement is prominent, in particular the destruction of vertebral bodies and the femoral heads. We describe studies in two siblings with ML III that suggest the presence of a distinct metabolic bone disorder. Biochemical indices of bone turnover were increased, and transiliac bone biopsy demonstrated both trabecular osteopenia and marked subperiosteal bone resorption. Intravenous pamidronate treatment given monthly for a year was well tolerated and produced dramatic clinical effects, with reduction in bone pain and improvements in mobility, despite incomplete suppression of bone resorption as assessed by biochemical, radiographic and histological criteria. Bisphosphonate therapy may have an important role in the management of bone pain in ML III, as it does in the related lysosomal disorder of Gaucher disease.     

Chronic recurrent multifocal osteomyelitis: a case report

Chronic recurrent multifocal osteomyelitis (CRMO) is a recognized condition that usually affects children and adolescents. It's characterized by insidious onset of local swelling and pain in affected bones. Clinical, biological and especially radiological abnormalities are suggestive of septic osteomyelitis, so the diagnosis is delayed. Bone biopsy with culture is certainly necessary to rule out bacterial osteomyelitis and bone tumor. Authors report the case of a 27-years old man in whom the diagnosis of CRMO was done after 14 years course.     

The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment

Summary: Mucolipidosis type III (ML III; McKusick 252600) is a rare lysosomal storage disease in which skeletal involvement is prominent, in particular the destruction of vertebral bodies and the femoral heads. We describe studies in two siblings with ML III that suggest the presence of a distinct metabolic bone disorder. Biochemical indices of bone turnover were increased, and transiliac bone biopsy demonstrated both trabecular osteopenia and marked subperiosteal bone resorption. Intravenous pamidronate treatment given monthly for a year was well tolerated and produced dramatic clinical effects, with reduction in bone pain and improvements in mobility, despite incomplete suppression of bone resorption as assessed by biochemical, radiographic and histological criteria. Bisphosphonate therapy may have an important role in the management of bone pain in ML III, as it does in the related lysosomal disorder of Gaucher disease.     

Systemic antibiotic therapy for chronic osteomyelitis in adults

The standard recommendation for treating chronic osteomyelitis is 6 weeks of parenteral antibiotic therapy. However, oral antibiotics are available that achieve adequate levels in bone, and there are now more published studies of oral than parenteral antibiotic therapy for patients with chronic osteomyelitis. Oral and parenteral therapies achieve similar cure rates; however, oral therapy avoids risks associated with intravenous catheters and is generally less expensive, making it a reasonable choice for osteomyelitis caused by susceptible organisms. Addition of adjunctive rifampin to other antibiotics may improve cure rates. The optimal duration of therapy for chronic osteomyelitis remains uncertain. There is no evidence that antibiotic therapy for >4-6 weeks improves outcomes compared with shorter regimens. In view of concerns about encouraging antibiotic resistance to unnecessarily prolonged treatment, defining the optimal route and duration of antibiotic therapy and the role of surgical debridement in treating chronic osteomyelitis are important, unmet needs.