Bone involvement in ISM, SSM, SM-AHNMD and ASM: More literature review (part 3)

A 2009 paper looked at prognosis of 157 ISM patients (Escribano 2009). 27% had bone involvement, with 18% patients having osteoporosis, 6% having diffuse bone sclerosis, 4% having patchy bone sclerosis 2% having small osteolysis and 3% having pathological fracture.

A 2012 paper (van der Veer 2012) assessed the frequency of osteoporosis and osteoporotic fractures in a group of 157 ISM patients. They found 28% had osteoporosis, with 27% having osteoporosis of the lumbar spine and 1% having osteoporosis of the hip. 4% had evidence of osteosclerosis.

43% of patients under 50 years old had had at least one fracture (osteoporotic or not) and 61% of patients over 50 years old had had at least one fracture. 27% of patients had one or more vertebral fractures and 21% had non-vertebral, osteoporotic fractures. 23% of male patients under 50 had osteoporosis as well as 38% over 50. 12% of women under 50 had osteoporosis as well as 33% over 50. In total, 37% had osteoporotic fractures. In the group with comorbidities that might cause osteoporosis or fractures, 49% had osteoporotic fractures and 37% had osteoporosis. 59% ISM patients without UP had osteoporotic fractures compared to 28% with UP.

A 2013 paper (Matito 2013) looked at the association of baseline serum tryptase with disease features, including progression to SSM or ASM. 74 patients with ISM were included in the study and were followed for at least 48 months. None of them received cytoreductive therapy. Patients with an increased serum baseline tryptase slope and those without significant tryptase increase had similar prevalence of osteoporosis, patchy bone sclerosis and diffuse bone sclerosis at both presentation and end of study. However, the group with increased serum baseline tryptase was more likely to develop diffuse bone sclerosis in the time span between the beginning of the study and the end of the study (13% vs 2% without significant tryptase increase).

Among the group with low serum baseline tryptase increase, 9% had osteoporosis at the start, and 14% at the end; 5% had patchy osteosclerosis at the end; 2% had diffuse bone sclerosis at the end. None in this group progressed to SSM or ASM.

Among the group with high serum baseline tryptase increase, 10% had osteoporosis at the start, and 16% at the end; 6% had patchy osteosclerosis at the end; 13% had diffuse bone sclerosis at the end. 13% progressed to SSM and 6% to ASM.

Four patients in this study progressed to SSM after the start of the study, in a time ranging from 8-85 months. All had serum baseline tryptase of at least 200 ng/ml and had increased serum baseline tryptase slope. They also had D816V CKIT mutation in cells other than mast cells. Two of these patients progressed to ASM. Both of these patients had diffuse bone sclerosis and swelling of both the liver and spleen. The authors of this paper recommend special attention to the development of hepatomegaly and splenomegaly and diffuse bone sclerosis.

 

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128: 344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Kushnir-Sukhov NM, Brittain E, Reynolds JC, Akin C, Metcalfe DD. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis. Int Arch Allergy Immunol. 2006;139(3):265-70. Epub 2006 Jan 30.

Matito A, Morgado JM, Álvarez-Twose I, Laura Sánchez-Muñoz, Pedreira CE, et al. (2013) Serum Tryptase Monitoring in Indolent Systemic Mastocytosis: Association with Disease Features and Patient Outcome. PLoS ONE 8(10): e76116. doi:10.1371/journal.pone.0076116

Escribano L, A lvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish network on mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514–521.

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Literature review (part 2)

There have been several publications on bone involvement in SM. Importantly, not all of these papers define SM the same way. Some define it as ISM, while others define it as ISM, SSM, SM-AHNMD and ASM. (I personally am sloppy about not specifying when I mean ISM versus when I mean any all the systemic proliferative groups. So if it’s not clear, please ask.) Another thing to be aware of is that the terminology for osteosclerosis is not consistent. It is sometimes referred to as osteocondensation (this is primarily a term used by French researchers). I have done some digging recently on this and cannot find any indication that these two terms do not represent the same phenomenon (increased deposition of bone), so if anyone knows of any papers or sources that say they are different, please let me know.

A 2010 paper (Barete 2010) defines SM as ISM, SSM, SM-AHNMD and ASM. They divided the study into two groups: Variant 1 (non-aggressive), ISM and SSM; and Variant 2 (aggressive), SM-AHNMD and ASM.

Overall (ISM, SSM, SM-AHNMD and ASM), 49% of patients had some form of bone involvement. Osteoporosis was most common, occurring in 31% of patients. 17% had a vertebral fracture. 8% had osteosclerosis. 4% had a mixed pattern, so more than one type of bone involvement. 5% had osteopenia with a previous fracture (this could be unrelated to mast cell disease, like an arm broken in a fall). Only one patient had a focal area of osteolysis with spontaneous fracture.

56% of variant 2 (aggressive) group had osteoporosis, compared to 23% of variant 1. However, when they excluded people who were classified as variant 2 based upon bone involvement, the association dropped to 17% variant 2 with osteoporosis and 23% of variant 1. Osteoporosis associated with vertebral fracture affected 48% variant 1 and 8% variant 2. Osteoporosis was also found to be associated with fewer GI symptoms, with 39% variant 1 having GI issues while 65% variant 2 did.

A total of six patients (out of a total group of 75) had osteosclerosis. One ISM, one SSM, three ASM and one SM-AHNMD patient had osteosclerosis. This translates to two in the variant 1 group and four in the variant 2 group, so twice as many in the aggressive group (ASM, SM-AHNMD) as in the non-aggressive group. 66% of patients in variant 2 with osteosclerosis had a blood count abnormality (anemia, thrombocytopenia, eosinophilia) vs 12% in variant 1. 83% of patients in variant 2 with osteosclerosis had received cytoreductive therapy vs 33% in variant 1, and higher tryptase level was associated with osteosclerosis. Overall, this means that osteosclerosis was associated with a more severe disease presentation (a patient with ISM and osteosclerosis may have a blood count abnormality), but this study does not provide any insight as to whether osteosclerosis is a marker associated with progression toward ASM or SM-AHNMD.

A 2011 paper (Guillaume 2011) assessed bone involvement in a group of CM and SM patients. In this study, SM included ISM, ASM and SM-AHNMD. 45 patients were included.  They found one patient with osteolysis, eight with osteocondensation (a form of osteosclerosis), four with a mixed pattern and three with fractures. They found no association between the presence of radiologic lesions (lesions detected by imaging techniques) and severity (here classified as non-aggressive: ISM and CM, and advanced: ASM and SM-AHNMD).

This study also looked at chemical markers used for bone remodeling. They found that markers associated with both bone resorption and bone formation were higher in mastocytosis patients than in the general population. The higher levels were thought to represent increased number of osteoblasts and osteoclasts due to the increase in mast cells. Osteoprotegerin was also higher in mastocytosis patients. This is a protein released by osteoblasts that regulates the activity of osteoclasts. Levels of C-telopeptide were significantly higher in patients with SM-AHNMD or ASM than in patients with ISM or CM.

A 2011 paper (Rossini 2011) investigated the relationship between tryptase and bone turnover markers (bone specific alkaline phosphatase, C-telopeptide, osteocalcin) in ISM patients. A total of 82 patients were enrolled in the study. 36% had bone involvement. 20% had osteoporosis, with 18.7% found in the spine and 2.5% at the hip. Five patients had a history of bone breaks outside of the spine. 27 patients had vertebral fractures. Two patients had osteosclerotic features and also had particularly high tryptase levels. Another study previously reported that high tryptase can be associated with increased bone density (Kushnir-Sukhov 2006).

This study had a large amount of ISM patients without skin lesions (55%). A very important finding of this particular study was that ISM patients without skin lesions are at the same risk for osteoporosis. As lesions are often one of the more identifiable markers of mastocytosis, the author raises the very valid point that osteoporosis may in some people be the only sign of latent ISM.

This paper reported that “diffuse osteosclerosis associated with SM is not a[n] “osteopetrosis-like osteopathy”, as previously reported, but a skeletal disease characterized by increased bone turnover.” This is important, as they have previously been equated for lack of distinction. The author further notes that the “pathophysiology of SM-related osteosclerosis remains obscure, although it is known that MCs can exert a direct stimulatory effect on osteoblast proliferation, recruitment, and activity.”

This study found that bone mineral density and serum tryptase did not correlate with the serum markers of bone turnover. However, it did find that ISM patients with osteosclerosis had higher tryptase and bone turnover markers (bone specific alkaline phosphatase and C-telopeptides of type I collagen) than ISM patients with other types of bone involvement.

(Literature review continued tomorrow)

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128:344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Kushnir-Sukhov NM, Brittain E, Reynolds JC, Akin C, Metcalfe DD. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis. Int Arch Allergy Immunol. 2006;139(3):265-70. Epub 2006 Jan 30.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Progression of mast cell diseases: Part 1

Among mast cell patients, we generally assume that a designation of SM means indolent systemic mastocytosis (ISM.) However, in research papers, this term can mean ISM, SSM, ASM or MCL. Advanced SM usually means ASM or MCL. These terms generate a lot of confusion in the patient population. When reading a paper, abbreviations are usually defined on the first page or within the introduction. It is important to check on what the researchers are using the term SM for.

As an example, let’s look at this really alarming quote to someone who thinks SM means ISM:

“The life expectancy of SM patients was shorter relative to age- and sex-matched controls. As initially observed by Travis et al, survival decreased rapidly after diagnosis: to 60% at 3 years, with a subsequent slower decline to 50% at 5 years. Beyond 5 years, the slope of the survival curve was similar to that of the control population. This observation confirms that the deaths in SM patients within the first 3 (and up to 5) years after diagnosis.” (Lim 2009)

In this paper, SM meant ISM, SM-AHNMD, SSM, ASM and MCL. When you average those survival rates together, you get a sharp decline in survival for the first five years. After that, it returns to normal, because most of the ASM and MCL patients in that study died by that time.

 

I get asked A LOT about whether or not ISM is progressive. I see a lot of people describe it as progressive. In medicine, progression usually means moving from one diagnostic category to a more serious one (like ISM to SSM.) However, a lot of patients use this term to mean a worsening of symptoms or disability while staying in the same diagnostic category (like ISM with mild daily symptoms to ISM with severe daily symptoms). Those are two different things. I’m going to answer both.

 

What is the life expectancy with ISM?

It’s normal.

“Patients with ISM have a favorable prognosis. These patients may suffer from mediator-release symptoms, but do not suffer from significant organopathy caused by MC infiltration.” (Valent, 2003)

In a study of 159 patients, 2.2% ± 1.3% died within five years of diagnosis, and 11% ± 5.9% died within twenty five years of diagnosis. “The majority of deaths in this ISM cohort were unrelated to mastocytosis.” (Pardanini 2013)

In a study of 342 patients, ISM was the largest subgroup with 159 patients.  They were significantly younger at presentation (median age 49 years.) “Overall median survival was not significantly different than that of the age and gender matched control population. Advanced age was the primary determinant of inferior survival.” (Pardanini 2013)

 

Will my ISM symptoms get worse with time?

There is really no way to know. In some people, they are stable, while in others, they fluctuate. However, mediator release symptoms (degranulation symptoms) are known to be more common in ISM than ASM and MCL.

“ISM patients can be highly symptomatic; in one study, 70% reported at least some degree of functional limitation, of which 17% reported severe limitation.” (Pardanini 2013)

“The type and severity of symptoms were independent of disease classification (CM vs SM), KITD816V status, and serum tryptase level.” (Pardanini 2013)

 

If my ISM symptoms get worse, does that mean I am progressing to a more severe category, like SSM, ASM or MCL?

No.

“One important aspect in this regard is that mediator-related symptoms per se are not indicative of aggressive mastocytosis unless accompanied by C-findings.” (Valent 2003)

“Moreover, organomegaly per se is not necessarily indicative of aggressive SM.” (Valent 2003)

“In fact, in a group of patients with SM, organomegaly is recorded over many years without impairment of organ function or development of C-findings.” (Valent 2003)

“The type and severity of symptoms were independent of disease classification (CM vs SM), KITD816V status, and serum tryptase level.” (Pardanini 2013)

 

References:

Pardanini, Animesh. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) 2013; Blood: 121 (16).

Pardanini, Animesh. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. 2013; American Journal of Hematology: 88 (7).

Pardanini, Animesh. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. 2009; Blood: 114 (18).

Lim, Ken-Hong, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. 2009; Blood: 113 (23).

Valent, Peter, et al. How I treat patients with advanced systemic mastocytosis. 2010; Blood: 116 (26).

Matito, Almudena, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. 2013; PLOS One.

Sperr, Wolfgang. Diagnosis, progression patterns and prognostication in mastocytosis. 2012; Expert Review of Hematology: 5 (3): 261-274.

Valent, Peter, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. 2003; Leuk Res 27 (7): 635-41.

Hauswirth, Alexander, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. 2004; Leuk Res 28 (3): 249-257.