REVIEWS
Pharmacological Treatment in Calcinosis Cutis
Associated with Connective-Tissue Diseases
ALINA DIMA1, P. BALANESCU1, C. BAICUS1, 2
1
“Colentina” Clinical Hospital, Bucharest, Romania
“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
2
Background. Dystrophic calcinosis cutis is a common manifestation in connective tissue
diseases, but there’s still no consensus on treatment.
Objectives. The purpose of this review is to discuss the current pharmacological options of
treatment in calcinosis cutis related to rheumatic diseases.
Method. We performed an extensive MEDLINE search of articles from 1970 to January 2014
using the index word “calcinosis” and the co-indexing terms “treatment”, “calcium channel blocker”,
“diltiazem”, “nifedipine”, “verapamil”, “amlodipine”, “anticoagulant”, “warfarin”, “bisphosphonate”,
“etidronate”, “pamidronate”, “alendronate”, “risedronate”, “aluminum hydroxide”, “probenecid”, “antibiotic”,
“tetracycline”, “minocycline”, “ceftriaxone”, “colchicine”, “intravenous immunoglobulin”, “sodium
thiosulfate”, “TNF-alpha inhibitors”, “infliximab”, “rituximab”, “thalidomide”, “corticosteroids”, “stem
cell transplantation”.
Results. Diltiazem is recommended by some authors as first-line approach in calcinosis cutis
and is also the therapeutic principal referred by the largest number of available publications. It seems
to be efficient in more than half of the reported cases. There remain, however, a significant number of
patients in which another solution must be found.
The general trends observed over time are of switching the search of solutions in dystrophic
calcinosis cutis related to connective tissue diseases, from therapies on calcium metabolism to
therapies for the underlying disease. The new options available in the management of calcinosis cutis,
like biological therapies or intravenous immunoglobulin, seem to be promising, but not universally
successful. In children with severe forms, hematopoietic stem cell transplantation can also be taken
into consideration.
Conclusions. Data for all therapies proposed in calcinosis cutis is generally reported in single
cases and small case series and so, the existent data is all yielding a low level of evidence.
Key words: calcinosis, dermatomyositis, systemic sclerosis.
INTRODUCTION
Calcinosis cutis (CC) is a rare disorder
characterized by abnormal insoluble calcium salts
deposition in soft-tissues, frequently in the fingertips
and periarticular region, but any area can be affected.
The classification of soft-tissue calcifications
includes metastatic calcification, tumoral calcification,
dystrophic calcification and idiopathic calcifications.
For some authors, calciphylaxis is also included
into calcinosis cutis [1].
Dystrophic calcinosis appears in patients with
normal calcium metabolism (normal serum levels
of calcium and phosphorus). It is associated with
connective tissue diseases (CTD), but also with
cutaneous neoplasm (pilomatricoma, trichilemmal
cyst), collagen and elastin disorders (pseudoxanthoma elasticum, Werner syndrome, Enhlers-Danlos
ROM. J. INTERN. MED., 2014, 52, 2, 55–67
syndrome), porphyria cutanea tarda or pancreatic
panniculitis [2].
Among rheumatic diseases, CC is more
frequently associated with dermatomyositis (DM),
being diagnosed in 44% up to 70% of children and
20% of adults [3]. Also, CC is not a rare manifestation in systemic sclerosis (SS), either 25% to
40% of patients with limited SS presenting subcutaneous calcifications [4]. Although uncommon,
CC may develop in systemic lupus erythematosus
(SLE), generally in asymptomatic and with longstanding disease patients [5]. CC was rarely found
also in mixed tissue connective disease (MTCD)
[6, 7], or Sjogren’s syndrome (S’sS) [8, 9].
Regarding the pathogenesis of CC in CTD, it
is not so clear if it is just a response to a local injury
like structural tissue damage, recurrent micro-trauma,
destruction in the collagenous and fat tissue or if it
56
Alina Dima, P. Balanescu, C. Baicus
is a specific manifestation of the underlying disease
[2]. Clinically, it may be present as benign limited
subcutaneous nodules that can be an incidental
radiologic finding or as multiples nodules, large
plaques of calcium deposits, either mobile or affixed to
the deep planes. Calcium deposits of CC may
ulcerate to the skin and discharge white, chalky
materials. Complications like inflammation, infections,
atrophy, issues of aesthetic and functional impotence
occur secondarily to CC [1].
Bowyer et al. classified the calcium
deposition in patients with DM into five types:
small and hard plaques or nodules just below the
skin surface, large tumoral deposits of calcium that
are popcorn-like on the radiographic examination,
deposits in the intramuscular fascia that limit
movement in the involved muscle group, a severe
form of dystrophic calcification that resembles an
exoskeleton, and mixed form of calcinosis [10].
Although a common manifestation in some
CTD, no treatment has been generally accepted as
standard therapy. The cause of this is lack of
evidence for a clearly effective treatment. Regarding
this subject, we have until now only reports from
single cases or small case series. Available data is
only level IV of evidence [11].
Chander S tried to separate the therapeutic
strategies applied in CC into three groups: therapies
for the underlying disease (considering CC proportional with the activity of the underlying disease),
therapies that act on calcium metabolism and the
mechanical removal of the calcified lesions [12].
In this article we only review the pharmacological treatment of calcinosis cutis. We are not
taking into analysis the non-pharmacological
treatments that are also proposed in CC, like
surgical excision, carbon dioxide laser, extracorporeal
shock wave lithotripsy or acetic acid iontophoresis
and ultrasound [13].
LITERATURE REVIEW
We performed an extensive MEDLINE
search in January 2014 in order to review all the
articles on the pharmacological treatment of
dystrophic calcinosis in CTD, using the index word
“calcinosis” and co-indexing terms related to the
alternatives of treatment. In Table I we tried to
chronological summarize the available pharmacological treatments proposed for CC.
2
CALCIUM CHANNEL BLOCKER
The calcium channel blocker diltiazem is
probably the most used medical treatment in CC
until now. The positive response of diltiazem was
initially reported in the 90’s in a patient with
CREST syndrome when the amelioration of calcium
subcutaneous deposits under this treatment was
confirmed by bone radiographs and scans [14]. The
efficacy of diltiazem was explained by its capacity
in reducing cellular calcium influx in the affected
tissues and also in the local macrophages [15].
Diltiazem manages to improve partially or
completely calcium deposits in more than half of
the total reported cases where this treatment was
used. (see Table I) Positive effects of the diltiazem
treatment were noticed in dystrophic CC associated
with different CTDs like DM [16-19], SS [14, 15,
20-22], MCTD [7, 19], SLE [23], lupus panniculitis
[24] or S’sS [9]; hence the benefits of diltiazem in
CC appeared to be independent of the underlying
pathology.
There is also published data that questions
diltiazem efficiency for CC. Vayssairat et al.
reported minor radiological improvement in only 3
out of 12 patients treated with diltiazem. The
authors hypothesized that diltiazem efficiency
might be dose related as this study used lower
doses (180 mg/day) than previously reported in
other studies [25]. Bertorini et al. reported benefits
in 3 out of 4 patients treated with diltiazem in the
span of a year, with higher doses, ranging from 240
to 480 mg/day [26]. Regarding the existing published
data, we cannot say if the success of diltiazem is
effective only in some selected patients or if it is
actually dose depending. Carocha et al. reported a
case where diltiazem was ineffective even in a dose
of 240 mg/day in a patient with SLE [27] and
Tristano et al. observed a poor response after three
months treatment with diltiazem [28].
In responder patients, the diminution of
calcium deposits might be observed relatively
quick, after months of treatment [9, 23, 29]. The
treatment with diltiazem was maintained with
positive results for many years in several cases [14,
18, 19]. The benefits of an initially effective treatment
seem to last even after the end of treatment, maximum period of follow–up reported being 12 years
[21].
Diltiazem was observed to be effective not
only in single administration, but also in thera-
3
Pharmacological treatment in calcinosis cutis
peutic association with other therapies proposed in
dystrophic CC. Oliveri et al. reported benefits for
diltiazem associated with bisphosphonates [30],
and Sharma NL et al. for diltiazem associated with
aluminum hydroxide [20]. The success of diltiazem
in patients that had also treatment with corticosteroids was noted in some publications [7, 16, 18,
23, 29].
Balin et al. presented the largest cohort of
patients with CC in CTD, a retrospective report
regarding 78 patients. They recommend diltiazem
which was efficient in their series in 9 out of
17 patients, as first-line approach therapy in
dystrophic CC [31].
The use of other calcium channel blockers
was much more rarely reported. Verapamil seems
to be less effective than diltiazem [21]. In the
retrospective analysis of Balin et al., one patient
improved under amlodipine treatment [31]. This
might be a solution in patients with cardiologic
contraindications for diltiazem.
LOW-DOSE ORAL ANTICOAGULANT
Vitamin K is known to be involved in
calcium binding processes in bones or tissues,
abnormally high levels of serum vitamin K being
observed in patients with CC, followed by normalization after beginning of warfarin therapy [32].
γ-Carboxyglutamic acid (GIa) that has
calcium and phospholipid binding properties is
expressed normally in bone and absent in nonmineralized soft tissue; it was also identified in soft tissue,
but only in association with ectopic calcifications [33].
Increased levels of matrix GIa protein (MGP)
have been measured in areas of calcinosis cutis
[34] and also in regions with vascular fibrosis or
calcifications [35].
Lian et al. found a 3-fold increase in Gla
excretion in patients with juvenile DM and CC and
a 2-fold increase GIa excretion in patients with
juvenile DM without calcifications or in patients
with various connective tissue disorders and
subcutaneous calcification [36].
On the contrary, Lassoud et al. report the
failure of warfarin treatment [37]. It was supposed
that carboxylated MGP might actually have a
protective role against CC and so warfarin treatment
cannot be useful in CC [11]. In general, we do not
have much certitude about the treatment of CC,
whether the fluctuation with time is the natural
evolution of CC or some of the treatments used are
truly effective? [7].
57
One study that tried to enlighten the utility of
warfarin was that of Berger et al., a double-blind
placebo study with the following results: two out of
three patients receiving 1 mg per day of warfarin
had decreases in extra-skeletal nuclear tracer
uptake after 18 months, compared with none of the
four patients receiving placebo. The authors found
a diminished GIa urinary concentration, a mechanism
that might explain the decreased extra-skeletal
uptake, on technetium 99m-diphosphonate wholebody nuclear scanning. Also, in this study the
treatment with low-dose warfarin appeared to be
well tolerated, with no demonstrable adverse effects
[38]. Cukierman et al. reports positive effects of
treatment with warfarin 1mg/day in 2 out of
3 patients treated for 12 months [39]; Yoshida et al.,
respectively Matsouka et al. presented other two
case reports where warfarin was useful for
treatment of dystrophic CC [32, 40].
On the other hand, Moore et al., who
included in their study not only patients with
subcutaneous calcifications, but also patients with
muscular calcifications, did not observe any clinical
benefits of warfarin treatment in CC even if the
urinary excretion of Gla was reduced in all patients.
Also, two patients experienced hemorrhagic complications during therapy [41] Balin et al. found
improvement under warfarin treatment in only one
out of four patients with CC [31], while Schantz et al.
presents one case of CC that did not respond to
warfarin treatment [42].
As for the other therapies proposed in CC, the
data regarding the use of low-dose oral anticoagulant is contradictory; no study on this topic
was published recently (see Table I).
BISPHOSPHONATES
Bone resorption was observed to be increased
in patients with CTD which associate dystrophic CC.
This can be a source of calcium for further deposition
into soft tissue; the attempt of diminishing bone
turnover might be useful in patients with CC [43].
Bisphosphonates, by their principal mechanism of
action, reducing bone resorption and inhibition of
calcium turnover, might interfere with CC forming.
Bisphosphonates were proved to have effect on
inhibiting ectopic calcifications [44].
Macrophages, IL-6, IL-1β and TNF-α were
found in the samples of collection from CC and
detectable levels of IL-1β in the serum of patients
with CC. The inhibition by bisphosphonates of local
macrophages and secondarily of local cytokine
production might explain the anti-inflammatory
58
Alina Dima, P. Balanescu, C. Baicus
effects of bisphosphonates in CC. Another aspect
that is not clear is how bisphosphonates may
remove calcium deposits already constituted. It was
hypothesized that bisphosphonates bound with
calcium are taken up by macrophages, interfere
then with macrophage cell lineage thus causing a
selective destruction of macrophages [45].
The data about the usefulness of firstgeneration biphosphonates etidronate in dystrophic
CC is conflicting. Metzger [46] et al. and Saunders
Jr [47] et al. reported failure in improvement of CC
with etidronate in 6 patients with DM and
scleroderma, respectively in one patient with
CREST syndrome. On the contrary, Rabens et al.
noticed improvement of CC with etidronate in
patients with scleroderma [48]. Positive response
was achieved with etidronate in the case of a
10-years old girl with juvenile DM, but the authors
reported also occurrence of focal defect of
mineralization [49] Etidronate was safely used for
6 months post-operatively in a patient with SLE in
order to maintain remission after CC’s surgery
[50].
Recently, Mori et al. proposed, with good
therapeutic results, etidronate as the bisphosphonate
of choice in CC taking into account its lack of
selectivity for bone and its capacity to concentrate
in other tissues than bone [51].
Pamidronate in intravenous administration
was reported as being effective for dystrophic CC
treatment practically in the majority of cases
published until now; unfortunately, we have only
some case reports [30, 52-55].Only one article
reports pamidronate failure [56], while other
reveals that the possible benefit of pamidronate is
not completely ruled out [57].
Marco Puche et al. obtained positive response
in 3 patients with juvenile DM, concluding that
pamidronate in conjunction with good disease
control with DMARD therapy is an apparently safe
and effective treatment for CC management [52].
Pamidronate was effective in patients where
other therapeutic options failed, Terroso et al.
reported positive response after failure with
colchicine, diltiazem, probenecid, alendronate [54]
and Martillotti et al. after failure with IVIG,
rituximab, colchicine [55]. The results seem to be
stable over 5 years [53], respectively 8 years [54]
of follow-up without relapse being reported.
In the retrospective analysis of Balin et al.,
the treatment with alendronate was not effective in
any of the 3 patients to whom it was administered
[31]. On the contrary, Mukamel et al. report two
cases of CC associated with juvenile DM with
4
positive results under alendronate treatment [45],
and Ambler et al. report positive response after
failure with diltiazem or probenecid treatment [58].
Another third-generation bisphosphonate,
risedronate, was noticed as being effective also for
CC, when introduced for osteoporosis in a patient
with CC evolving for 3 years [59].
The anticalcification potency was measured
and appears to be the same for Alendronate and
Pamidronate [60]. Nitrogen-containing bisphosphonates might have superior efficiency than old
non nitrogen-containing bisphosphonates in ectopic
calcifications, as the newest bisphosphonates interact
with signaling molecules involved in regulation of
cell proliferation, cell survival, and cytoskeletal
organization [61].
ALUMINUM HYDROXIDE
Aluminum hydroxide was initially proposed
as treatment in tumoral calcinosis, a related
disorder associated with hyperphosphatemia [4].
Aluminum hydroxide binds phosphorus, and also
decreases intestinal phosphorus absorption [62].
Hydroxyapatite was found in subcutaneous deposits
of dystrophic calcinosis, so a diminished phosphorus intake might ameliorate calcium deposits
also in other types of calcinosis besides those
associated with hyperphosphatemia [63].
One of the first cases of dystrophic calcinosis
responsive to aluminum hydroxide was presented
in early 1970 in a patient with juvenile DM [64].
Also, other case reports referred to the benefits of
aluminum hydroxide in calcinosis [65-68]. However,
more recently reports described aluminum hydroxide
failure [16, 27]. Administration of aluminum
hydroxide together with one of the other therapies
proposed in CC was proven to be successful, like
the association with Probenecid [69], Diltiazem
[20] or together with surgical excision [70]. Another
aspect is that a low-phosphorus diet can be used
together with the treatment, helping the decrease of
the urinary phosphorus excretion and the increase
of the urinary calcium excretion [71].
PROBENECID
Probenecid is known as an inhibitor of uric
acid reabsorption in the proximal tubule. It appears
to have also an effect on increasing renal phosphate
clearance, being so useful in calcinosis management [72]. Like other therapies proposed in
calcinosis, Probenecid showed efficiency in CC but
5
Pharmacological treatment in calcinosis cutis
only isolated case reports have been published until
now [73–75]. Other reports regarding the probenecid use in CC associated with DM were negative
[54, 58].
More recently, Nakamura et al. described
remarkable improvement of calcinosis in a patient
with juvenile DM after 17 months of administration;
it is also noted that clinical improvement was
accompanied by normalization of serum phosphorus
level and disability (for this particular case report,
the diagnosis of dystrophic CC was debated as by
definition the levels of phosphorus are normal in
dystrophic calcinosis) [76].
MINOCYCLINE
Minocycline belongs to tetracyclines group of
antibiotics. Teteracyclines have more than antibacterial properties with biologic actions affecting
inflammation, proteolysis, angiogenesis, apoptosis,
metal chelation, ionophoresis, and bone metabolism
[77]. When trying to estimate the anticalcification
capacity of tetracycline, this seems to be smaller
than that of bisphosphonates [60].
Robertson et al. presented the results of a
clinical study on utility of minocycline in dystrophic
calcinosis. Nine patients with CC in lSS were
treated with 50-100 mg minocycline/day for a
mean of 3.5/-1.9 years. Eight patients have shown
definite improvement for frequency of ulceration
and inflammation associated with calcium deposits
and only slight improvement in the size of the
calcinosis deposits. A strange accompanying phenomenon was noticed: change of color from white to
blue/black in calcium deposits of patients treated
with minocycline [78]. The formation of blue
subcutaneous nodules secondarily to tetracyclines
treatment was initially observed in a patient treated
for acne. Examination of the osteomas suggested
that tetracycline causes the pigmentation of osteoma
cutis [79].
CEFTRIAXONE
Ceftriaxone is another antibiotic proposed for
the treatment of CC taking into account its antiinflammatory and calcium binding properties.
Secondary effects of ceftriaxone involving calcium
metabolism like biliary pseudolithiasis and nephrolithiasis are well known.
Improvement of calcinosis cutis with ceftriaxone treatment was observed after 20 days of
59
intravenous administration, 2 g/day in a 16-years
old boy with a 2-year history of multiple asymptomatic, subcutaneous, firm nodules in the context
of a possible idiopathic calcinosis cutis. In the case
of this patient, initial treatment with aluminum
hydroxide was inefficient [80].
COLCHICINE
Colchicine was proposed as treatment in CC
due to its anti-inflammatory effects, with possible
benefits in the context of crystalline, hydroxyapatite-induced associated inflammation. Taborn
et al. presented the case of two patients with juvenile
DM in which local and general signs of inflammation
positively responded under colchicine treatment
[81]. Colchicine seems to be more useful in local
inflammation regression and healing of skin
ulcerations than in effectively diminishing calcium
deposits [82, 83]. Other authors report failure of
colchicine treatment in CC [54, 58]. In the retrospective analyses of Balin et al., positive responses
were noticed in three out of eight patients, from
which one patient recorded complete response with
total resolution of calcium deposits. The authors
proposed colchicines as a second recommendation,
after calcium-blockers, for CC’s treatment [31].
INTRAVENOUS IMMUNOGLOBULIN
Intravenous immunoglobulin (IVIG) has been
gaining more attention in the past years for indications
in the rheumatologic diseases. Schanz et al. reported
remarkable reduction of inflammation, tissue damage,
and firm masses in CC after IGIV treatment [42].
Afterwards, other three case reports supported the
idea that IVIG might be useful in patients resistant
to conventional therapies proposed for CC [57, 83,
84]. Peñate Y et al. reported well outcome in a
55-years old woman non-responsive to Diltiazem
treatment, Shahani et al. reported positive evolution
in a case of a 30-year old woman with DM [85],
and Touimy et al. reported good outcome in a 10years old boy with juvenile DM, previously successively non-responder to pamidronate, cyclosporine,
diltiazem, alendronate, probenecid, colchicine [57].
As for other possibilities of treatment in CC,
the positive response does not seem to be
universally valid, cases of failure to IVIG can be
also found in current literature [18, 86, 87] (see
Table I).
60
Alina Dima, P. Balanescu, C. Baicus
SODIUM THIOSULFATE
Sodium thiosulfate increases calcium solubility
and has been successfully used to treat calciphylaxis with little to no adverse effects [88, 89].
Topic administration of sodium thiosulfate
was also used in dystrophic CC. The thiosulfate
capacity in dissolving calcium was mandatory
especially in the presence of chronic ulcers secondarily to subcutaneous deposits. Sodium thiosulfate
manages to promote wound healing probably
because the calcium deposits impair normal regrowth
of epithelial tissue across the open wounds [90].
Topical administration with good results was
reported in calcinosis [91] and in CC secondary to
DM [92]. Intradermal injection with eventual
clearance of calcium deposits after 3 administrations
was also reported in DM [93]. Arabshahi et al.
presented the case of a 14-year old boy for which
intravenous sodium thiosulfate, in addition to the
topical apply, was safely administered. Abatacept
was concomitantly given to this patient. It is
emphasized that thiosulfate might have a role in
stabilizing calcinosis, in diminishing pain and
promoting re-vascularization of cutaneous ulcerations
[87].
BIOLOGICAL THERAPY
The examination of fluid collection from the
CC lesions of two patients with juvenile DM
showed the presence of macrophages, IL-6, IL-1,
and TNF-alpha [45]. TNF-alpha-308A promoter
polymorphism that increased TNF-alpha production
of peripheral blood mononuclear cells seems to be
more frequently present in patients with CC [94].
Chander S et al. presents the first cases of
juvenile DM complicated with CC treated with
infliximab. Improvements of pathology were seen
in all five patients as demonstrated by the disease
activity scores between 8 and 30 months after
starting infliximab. In four patients, the response of
CC was not complete, but the lesions were in
regression [95].
Recently, efficacy of infliximab in the case of
a refractory CC in a context of overlap limited SS
and myositis was presented. The infliximab was
administered at 0, 2, 6 weeks and afterwards every
8 weeks. The total follow-up was of 41 months, the
longest duration of treatment with anti-TNF-alpha
for CC in the current literature was reported in this
paper [96].
6
Daoussis et al. reported a significant improvement of CC in a 53-year old woman with CREST
following rituximab. This treatment was actually
administered for lung involvement in this patient
while the effect on calcinosis was rather unexpected
[13]. Another case of positive response for CC
under rituximab treatment was reported in the same
context, the regression of the calcium deposits in a
54-year old woman with CREST treated with antiTNF-alpha for the pulmonary pathology [97].
On the contrary, for CC related to juvenile
DM, the lesions did not improve in 6 out of
9 patients treated with rituximab and mild infections
of the calcinosis sites occurred in 2 patients. The
study concluded that rituximab may be effective in
treating muscle and skin involvement in a small
subset of children with severe juvenile DM, and
that its safety profile was satisfactory [98].
THALIDOMIDE
Thalidomide selectively inhibits mRNA
expression of TNFα and IL-6 in human peripheral
blood mononuclear cells [99]. Starting from the
same hypothesis about a possible benefit in CC for
thalidomide as for TNF-alpha inhibitors, Miyamae
et al. treated with thalidomide a 14-year old patient
with juvenile DM. The initial dose of 15 mg/day
(1.3 mg/kg day) was given for first four weeks, and
then it was increased to 75 mg/day. Thalidomide
demonstrated clinical and biological benefits, with
a better control of inflammation but without complete
response for CC. Examination by whole-body 18FFDG-PET-CT over the 15 months of thalidomide
treatment demonstrated fewer hot spots around the
subcutaneous calcified lesions [100].
INTRALESIONAL CORTICOSTEROIDS INJECTIONS
Administration of intralesional corticosteroids
may be useful in the diminution of local associated
inflammation and amelioration of calcium deposits
in CC. Intralesional triamcinolone diacetate (a total
of 250 mg during 1 year) showed benefits in a
13-year old boy [101].
Hazen PG et al. reported almost complete
resolution of CC in a patient with localized SS after
repeated injections of intralesional corticosteroids;
a second patient was also treated but he was
unavailable for follow-up [102].
7
Pharmacological treatment in calcinosis cutis
Another positive response with intralesional
corticosteroids was obtained in a patient with
juvenile DM non-responder in treatment with
colchicine and iv pamidronate. No relapse for CC
was observed over a 2-year follow-up post-injection
[56].
HEMATOPOIETIC STEM CELL TRANSPLANTATION
Maldelbrot et al. reported, in 2008, the
successful management with hematopoietic stem
cell transplantation (HSCT) of subcutaneous
calcifications in 3 patients with SLE (one with
calciphylaxis secondary to haemodialysis and two
with dystrophic CC) that failed to respond to prior
conventional therapies [103]. Other authors, Holzer
et al. also reported good results of autologous stem
cell transplantation in two patients with juvenile
DM. One patient, an 8-year old girl, also associated
calcinosis and three months after the intervention
the dissolution of calcifications was observed [104].
CONCLUSIONS
The treatment of CC, a pathology that can be
accompanied by significant discomfort and
disability, rests challenging. So far, data regarding
treatment of CC has only been generally reported
in single cases and small case series. No agent that
clearly prevents or ameliorates CC has been yet
identified.
The treatment with diltiazem is recommended
as first line approach [2]. Even so, in the largest
retrospective study realized in Mayo clinic on
78 patients only 9 patients showed amelioration for
61
the lesions of CC out of 17 patients treated with
diltiazem [31]. Therefore, there are many patients
for which other therapeutic solutions should be
found.
The information about the utility or the
mechanism of action of warfarin in CC is contradictory and there are not positive reports published
recently. Bisphosphanates, especially pamidronate,
showed positive results for the majority of patients
reported. Colchicine and minocycline seem to be
more effective on the inflammatory processes
associated with CC, than in effectively reducing
calcium deposits sizes.
The reports about new molecules introduced
for treatment in CC, like THF-alpha inhibitors or
IVIG are promising. Unfortunately, only few cases
have been published until now. In children with
severe forms, HSTC should also be taken into
consideration as an alternative of treatment.
We did not review the non-pharmacological
treatment of CC; surgery should be taken into
account in patients with limited, symptomatic
lesions of CC, especially as the results are immediately
observed. But surgery cannot be a solution in
patients with disseminated, extended calcium deposits
where only a systemic treatment rests as solution.
The treatment must always be tailored for
each particular patient, taking into account all
possibilities of treatment. Further research and
controlled studies are needed to find effective
solutions of treatment in CC.
Acknowledgments. This paper is supported by the Sectoral
Operational Programme Human Resources Development (SOP
HRD), financed from the European Social Fund and by the
Romanian Government under the contract number
POSDRU/159/1.5/S/137390.
Introducere. Calcinosis cutis distrofică este o manifestare obişnuită în bolile
de ţesut conjunctiv. Cu toate acestea, nu există încă un consens privind tratamentul
optim.
Obiective. Scopul acestui review este discutarea opţiunilor de tratament
actuale în calcinosis cutis asociată bolilor de ţesut conjunctiv.
Metodă. Am realizat o căutare MEDLINE extensivă a articolelor indexate
din 1970 până în ianuarie 2014 folosind termenul „calcinosis” şi asociat, succesiv
co-termenii „tratament”, „blocanţi de canale de calciu”, „diltiazem”, „nifedipină”,
„verapamil”, „amlodipină”, „anticoagulant”, „warfarină”, „bisfosfonat”,
„etidronat”, „pamidronat”, „alendronat”, „risendronat”, „hidroxid de aluminiu”,
„probenecid”, „antibiotic”, „tetraciclină”, „minociclină”, „ceftriaxonă”,
„colchicină”, „imunoglobuline intravenos”, „tiosulfat de sodiu”, „inhibitori
TNF-alfa”, „infliximab”, „rituximab”, „talidomidă”, „corticosteroid”,
„transplant de celule stem”.
62
Alina Dima, P. Balanescu, C. Baicus
8
Rezultate. Diltiazemul este recomandat de unii autori ca primă linie de
tratament în calcinosis cutis, fiind de asemenea principalul agent terapeutic
prezentat de cea mai mare parte a publicaţiilor. Acesta pare să fie eficient în mai
mult de jumătate de cazuri. Rămân însă un număr important de pacienţi la care o
altă soluţie terapeutică trebuie găsită.
În general, se poate observa tendinţa de modificare a abordării în căutarea
de soluţii în calcinoza distrofică din boli ale ţesutului conjunctiv, de la terapii
legate de metabolismul calciului la terapii pentru boala de fond. Noile opţiuni
terapeutice disponibile în tratamentul calcinosis cutis, ca terapia biologică sau
imunoglobulinele intravenos, par să fie promiţătoare, deşi nu eficiente în toate
cazurile. La copiii cu forme severe, transplantul de celule stem poate fi de
asemenea o soluţie.
Concluzii. Datele existente pentru terapiile propuse în calcinosis cutis sunt
în general raportări de prezentări de caz sau serii mici de cazuri şi astfel,
informaţiile existente au un nivel de relevanţă scăzut.
Corresponding author: Alina Dima, “Colentina” Clinical Hospital, Bucharest, Romania
No. 19-21 Stefan cel Mare Street, code 72272, Sector 2, Bucharest, Romania
Tel: +40729024568
E-mail: [email protected]
Potential conflict of interest: Nothing to report.
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Received May 9, 2014
66
Alina Dima, P. Balanescu, C. Baicus
12
1
1
1
DM
1
DM
Juvenile DM
DM
SS
SLE
MCTD
Overlap
UCTD
PM
RA
1
1
30/78
24/78
2/78
4/78
6/78
6/78
1/78
1/78
DM
Juvenile DM
1
1
DM
CREST
Juvenile DM
Juvenile DM
Limited SS
Sjogren’s syndrome
SLE
SS
SLE
1
1
9
1
1
1
Juvenile DM
2
Juvenile DM
Juvenile DM
3
1
Juvenile DM
1
Unknown CTD
1
Juvenile DM
DM
1
2
MTCD+PAN
Amyopathic DM
1
1
Juvenile DM
SLE
CREST
5
1
1
SLE
CREST
Juvenile DM
2/3
1
1
1
1
IGIV
Rituximab
Colchicine
Pamidronate
Infliximab
54
Rituximab
10
Pamidronate
Cyclosporine
Diltiazem
Alendronate
Probenecid
Colchicine
IGIV
25
Colchicine
Hydroxide Magnesium
Diltiazem
Alendronate
Probenecid
Pamidronate
37
Sodium thiosulfate
Sodium thiosulfate
Diltiazem
Amlodipine
Colchicine
Minocycline
IGIV
Etidronate
Alendronate
Warfarin
Methotrexate
26
Etidronate
14
Tacrolimus
IGIV
Sodium thiosulfate+Abatacept
30
IGIV +Methylprednisone
53
Rituximab
Rituximab
12
Diltiazem (+CS)
73
Diltiazem (+Salicylic Vaseline)
55
Diltiazem
9
Diltiazem (+CS)
17
Diltiazem + Aluminium Hydroxide
30
Diltiazem
Aluminium Hydroxide
8
IGIV
Rituximab
HSCT
Pamidronate
10.5 Colchicine
Pamidronate
Intralesional corticosteroid
14
Colchicine
Pamidronate
16
Aluminum hydroxide
Ceftriaxone
14
Thalidomide
Diltiazem
Hydroxychloroquine
Alendronate
IGIV
37
Diltiazem(+CS)
55
Diltiazem
IGIV
3-5
Infliximab
41
Sodium thiosulfate
56
Warfarin
Lithotripsy
IVIG
15-35-17 HSCT
51
Risendronate
11
Probenecid
1 mg/kg
3 mg/kg
375 mg/m2
2 g/kg
-
0/1
0/1
0/1
1/1
1/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
1/1
2014 Martillotti J et al.55
0.1 ml (12.5 mg/50ml)
800 mg/day
375 mg/m2
30 mg/day
300 mg/day
120mg/day
5 mg/kg
90 mg/day
240 mg/day
60 mg/day
-
1/1
1/1
9/17
1/1
3/8
1/6
0/6
1/2
0/3
1/4
1/1
1/1
0/1
0/1
1/1
1/1
1/1
3/9
1/1
1/1
1/1
1/1
1/1
0/1
2013 Smith GP93
2013 Pagnini I et al.92
2012 Balin SJ et al.31
0/2
0/2
2/2
3/3
0/1
0/1
1/1
0/1
1/1
0/1
1/1
1/1
0/2
0/2
0/2
0/2
1/1
0/1
1/1
5/5
1/1
0/1
0/1
1/1
2/3
1/1
1/1
2010 Holzer U et al.104
1 mg/kg
2 mg/kg
2 g/day
1.3 mg/kg
240 mg/day
200 mg × 2/day
70 mg/week
2 g/kg
90 mg/day
120 mg/day
0,4 g/kg
3 mg/kg
-
References
Overlap lSS/myositis
CREST
Juvenile DM
Year of
publication
7
Responders/
Total
1
Dose
Age
(years)
Juvenile DM
Therapy
Number of
patients
Underlying
disease
Table 1
Proposed treatments for calcinosis cutis associated with connective-tissue diseases
2013 Tosounidou S et al.96
2013 De Paula RD et al.97
2013 Touimy M et al.57
2013 Terroso G et al.54
2012 Mori H et al.51
2012 Arabshahi B et al.87
2012
2012
2011
2011
2011
2010
2010
2010
2010
Shahani L et al.85
Daoussis D et al.13
Bader-Meunier B et al.98
Jiang X et al.29
Ales-Fernandes M et al.22
Llamas-Velasco M et al.9
Donmez O et al.23
Sharma NL et al.20
Carocha AP et al.27
2010 Marco Puche A et al.52
2010 Al-Mayouf SM et al.56
2010 Slimani S et al.53
2010 Reiter N et al.80
2010 Miyamae T et al.100
2009 Kalajian MD et al.86
2009 Goolamali S et al.7
2009 Penate Y et al.84
2008 Riley P et al.95
2008 Wolf EK et al.90
2008 Schanz S et al.42
2008 Mandelbrot DA et al.103
2006 Fujii N et al.59
2006 Nakamura H et al.66
13
Pharmacological treatment in calcinosis cutis
SLE
Juvenile DM
1
1
DM
1
SS
Localized SS
Juvenile DM
3
9
1
Cutaneous LE
1
Juvenile DM
1
Juvenile DM
jDM
Juvenile DM
4
1
1
SLE
DM - MCTD
SS
DM
Linear scleroderma
jDM
jDM
1
2
47
1
2
1
Juvenile DM
Scleroderma
CREST
1
1
5
Juvenile DM
CREST/ SS
Juvenile DM
CREST
jDM
DM-SS
DM/ SS
Scleroderma-DMMyositis
SS-jDM
Juvenile Dm
Juvenile DM
Juvenile DM
CRST
Scleroderma
SS/DM
DM-scleroderma
Unknown CTD
SS
Juvenile DM
Juvenile DM
Overlap lSS/myositis
CREST
1
1
1
5-1
4
2-1-2
40
6
Diltiazem
240 mg/day
Diltiazem
Probenecid
Alendronate
61
Colchicine
Diltiazem
330 mg/day
35-30-70 Warfarin
1mg/day
66.2 Minocycline
50-100 mg/day
3
Aluminium Hydro
Diltiazem(+CS)
30 mg/day
Diltiazem
+Chloroquine
6
Diltiazem
Alendronate
10 mg/day
10.7 Diltiazem
6 mg/kg
9
Probenecid
15
IVIG
Diltiazem
360 mg/day
32
Aluminium hydroxide + surgery
600 mg × 3/day
32-40 Diltiazem
90-180-240 mg/day
56
Diltiazem
180 mg/day
27
Warfarin
Colchicine
1 mg/day
14-15 Aluminium hydroxide
19
Aluminum hydroxide
IGIV+Plaquenil+Aluminum hydroxide
7.5 g/day
Probenecid+Aluminum hydr(+Alendronate) 250 mg/day – 500 mg × 3/day
8
Diltiazem + Pamidronate
5 mg/kg + 4 mg/kg
62
Diltiazem
Diltiazem
240-480 mg/day
Verapamil
120 mg/day
3
Aluminium hydroxide
Warfarin
Aluminium hydroxide
Diltiazem
240 mg/day
13
Aluminium Hydroxide + Magnesium trisilica15-20 ml × 4/day (1.68-2.24 g/day)
Warfarin
1 mg/day
Warfarin
1 mg/day
Warfarin
-
1-1
1
1
2
1
1
1
3-3
1
1
1
1
10
9
14-13
46
45
23
64
9
7
1
1
54
Colchicine
Etidronate
Probenecid
Colchicine
Etidronate
Etidronate po
Aluminium hydroxide
Etidronate po
Probenecid
Probenecid
Aluminium hydroxide
IGIV
Rituximab
Colchicine
Pamidronate
Infliximab
Rituximab
1 mg/day
12 mg/kg/day
0.6mg x2-3/day
6.3 g/day
2 g/day
0.5-1.0g/day
15 ml × 4/day (2.4 g/day)
1 mg/kg
3 mg/kg
375 mg/m2
67
0/1
0/1
0/1
1/1
0/1
1/1
2/3
8/9
0/1
1/1
1/1
2006 Tristano AG et al.28
2005 Ambler GR et al.58
0/1
1/1
3/4
1/1
0/1
1/1
1/1
2/2
3/12
1/1
0/1
2/2
0/1
0/1
1/1
1/1
1/1
4/4
0/1
1/1
1/1
1/1
1/1
1/1
0/6
2/4
0/5
2001 Mukamel M et al.45
0/2
1/1
1/1
0/2
0/1
1/1
1/1
0/6
1/1
1/1
1/1
0/1
0/1
0/1
1/1
1/1
1/1
2005 Abdallah-Lotf M et al.17
2004 Cukierman T et al.39
2003 Robertson LP et al.78
2001 Ichiki Y et al.16
2001 Morgan KW et al.24
2001 Bertorini TE et al.26
2001 Harel L et al.72
2000 Vinen CS et al.18
1999
1999
1998
1998
1998
1997
1997
Park YM et al.70
Torralba TP et al.19
Vayssairat M et al.25
Matsouka Y et al.32
Vereecken P et al.83
Wananukul S et al.68
Eddy MC et al.69
1996 Oliveri MB et al.30
1995 Dolan AL et al.15
1995 Palmieri GM et al.21
1994
1993
1993
1990
1988
1988
1987
1986
Aihara J et al.67
Yoshida S et al.40
Nakagawa T et al.66
Farah MJ et al.14
Wang WJ et al.65
Lassaoued K et al.35
Berger RG et al.38
Moore SE et al.41
1986
1982
1981
1978
1977
1975
1974
1974
1972
1972
1970
2014
Fuchs D et al.82
Weinstein RS et al.49
Skuterud E et al.73
Taborn J et al.81
Saunders RL jr et al.47
Rabens SF et al.48
Hudson PM et al.71
Metzger AL et al.46
Dent CE et al.74
Mackie R et al.75
Nassim JR et al.64
Martillotti J et al.55
2013 Tosounidou S et al.96
2013 De Paula RD et al.97