Calcinosis cutis in autoimmune connective tissue diseases

Calcinosis cutis is a chronic condition involving insoluble calcified deposits of the skin and subcutaneous tissue. It is commonly associated with autoimmune connective tissue diseases and can be a source of pain and functional disability. The likelihood of developing calcinosis varies among the autoimmune connective tissue diseases, with systemic sclerosis and dermatomyositis being the most commonly associated. Identification of therapy for this challenging disorder has been hampered by a paucity of large controlled trials. Although there is no uniformly effective treatment for calcinosis cutis, several surgical and medical therapies have demonstrated varying degrees of benefit in the treatment of calcinosis, including surgical excision, laser therapy, extracorporeal shock wave lithotripsy, diltiazem, minocycline, colchicine, and topical sodium thiosulfate, along with others. Recommendations for the diagnosis and therapy of calcinosis cutis in patients with autoimmune connective tissue diseases are discussed.     

Dystrophic calcinosis cutis in subacute lupus

Dystrophic calcinosis cutis is known to be associated with various connective tissue disorders but to the best of our knowledge has never been reported in subacute cutaneous lupus erythematosus (SCLE), a distinctive cutaneous subset in the spectrum of lupus erythematosus. It occurs without calcium and phosphorus metabolic abnormalities and may be localized or generalized. We report a patient with SCLE who developed calcinosis cutis and had normal serum calcium and phosphorus levels and, interestingly, a normal concentration of blood ionized calcium. This latter, which represents the active form in the total amount of blood calcium, is a parameter only rarely assessed in patients with dystrophic calcinosis cutis. Thus, other pathogenic factors should be investigated to clarify the pathophysiology of the dystrophic type of calcification.     

PROPOSAL FOR A PATHOGENESIS-BASED CLASSIFICATION OF TUMORAL CALCINOSIS

Background. Deposition of calcium in skin is currently categorized into a group of disorders referred to as calcinosis cutis. Divisions between types and subtypes within this confusing classification are predominantly based on morphologic differences in the calcification and serve to obscure pathogenesis. This is especially evident in a subtype of calcinosis cutis, known as tumoral calcinosis. Calcifications in cases of tumoral calcinosis share the following characteristics, but without evidence of a common pathogenesis: large size, juxtaarticular location, progressive enlargement over time, a tendency to recur after surgical removal, and an ability to encase adjacent normal structures. The goal of this study was to formulate a pathogenesis-based classification for cases of tumoral calcinosis. Methods. In a literature review 121 cases of tumoral calcinosis were identified. These cases, along with a case evaluated in our clinic, were reviewed retrospectively, and their features compared. Results. Analysis suggests three pathogenetically distinct subtypes of tumoral calcinosis: (1) Primary normophosphatemic tumoral calcinosis: patients have normal serum phosphate, normal serum calcium, and no evidence of disorders previously associated with soft tissue calcification; (2) primary hyperphosphatemic tumoral calcinosis: patients have elevated serum phosphate, normal serum calcium, and no evidence of disorders previously associated with soft tissue calcification; and (3) secondary tumoral calcinosis: patients have a concurrent disease capable of causing soft tissue calcification. Justification for this classification is based on the presence or absence of disorders known to promote soft tissue calcification and statistically significant differences in family history, mean calcification number, mean serum phosphate level, and calcification recurrence after excision. Conclusions. A classification for tumoral calcinosis is devised that outlines potential pathogenetic mechanisms and predicts response to therapy and prognosis. Analysis of other forms of calcinosis cutis may reveal definable pathogenetic differences that suggest a coherent classification for all cutaneous calcinoses.     

Metastatic calcinosis cutis

Calcinosis cutis may be associated with metastatic calcification, dystrophic calcification, tumoral calcinosis, or may be deemed idiopathic. The association of cutaneous calcification with metastatic or tumoral calcinosis is quite rare. A case of metastatic calcinosis cutis in a woman with chronic renal failure and secondary hyperparathyroidism is presented. Other causes of calcinosis cutis are discussed briefly.     

Regression of cutis calcinosis with diltiazem in adult dermatomyositis

Calcinosis cutis is common in several connective tissue diseases such as dermatomyositis, scleroderma or lupus erythematous. In dermatomyositis, it is more likely to concern children than adults but it is not exceptional in adults. Several treatments have been used empirically with inconsistent success. We report a case of adult cutis calcinosis associated with dermatomyositis which responded dramatically to treatment with diltiazem.     

Lack of response to intravenous sodium thiosulfate in three cases of extensive connective tissue disease‐associated calcinosis cutis

Dystrophic calcinosis cutis is a debilitating condition of calcium salt deposition in the skin often occurring in association with connective tissue disease (CTD). Available treatments for calcinosis cutis are unsatisfactory, but given the recent use of topical and intralesional sodium thiosulfate (STS) to treat calcifying disorders, we sought to describe the use of intravenous (IV) STS for CTD‐associated dystrophic calcinosis cutis. We report three patients with long‐standing and extensive CTD‐associated calcinosis cutis treated with IV STS after having failed multiple prior therapies. All three patients experienced fatigue and nausea with STS infusions, and none of the patients had notable clinical or symptomatic improvement of calcinosis. It remains to be seen whether the administration of IV STS earlier in the onset of calcinosis might be of benefit given that these patients all had long‐standing and refractory CTD‐associated calcinosis. Given the small number of patients in this series, further investigation into the use of IV STS in calcinosis cutis is warranted.     

The relation between nailfold bleeding and capillary microscopic abnormality in pateints with connective tissue diseases

Background Patients with connective tissue diseases, mainly scleroderma, show nailfold bleeding and nailfold capillary abnormality. An attempt was made to determine the possible relation between nailfold bleeding and nailfold capillary abnormality.
Methods The correlation between nailfold bleeding and nailfold capillary abnormality was studied using quantitative nailfold capillary microscopy.
Results The frequencies of nailfold bleeding in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, and secondary Raynaud's phenomenon were significantly higher than those of normal controls. The distributions of abnormal values of capillary parameters in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, secondary Raynaud's phenomenon, primary Raynaud's phenomenon, and diabetes mellitus were significantly higher than those of normal controls. In normal controls, scleroderma, mixed connective tissue diseases, dermatomyositis/polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, primary Raynaud's phenomenon, and diabetes mellitus, all nailfold bleeding was observed in subjects with nailfold capillary abnormality. The distribution of nailfold bleeding in secondary Raynaud's phenomenon with abnormal values of capillary parameters was significantly higher than that with normal values.
Conclusions There is a close relationship between nailfold bleeding and nailfold capillary abnormality.     

Round fingerpad sign: an early sign of scleroderma

We describe a clinical skin sign in scleroderma termed round fingerpad sign. This term refers to disappearance of the peaked contour on fingerpads and replacement with a hemisphere-like fingertip contour; this change is especially apparent on the ring fingers. A positive round fingerpad sign was found in 72 of 72 ring fingers in 36 patients with progressive systemic sclerosis in 69 of 72 ring fingers in patients with mixed connective tissue disease, and in 24 of 24 ring fingers of patients with Raynaud's phenomenon and sclerodactyly. In contrast, a negative round fingerpad sign was seen in 240 of 240 fingers in normal women (controls). The high sensitivity of this sign is noteworthy. A positive round fingerpad was seen in sign not only typical scleroderma patients but also in groups with less severe skin sclerosis (i.e., in those patients with mixed connective tissue disease or those with Raynaud's phenomenon and sclerodactyly). The sign is a new and useful clinical marker for the early diagnosis of scleroderma.     

Longitudinal study of patients with anticentromere antibody

As has previously been reported by many investigators, the anticentromere antibody is considered to be a useful serologic marker for the CREST (calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly and telangiectasia) variant of systemic sclerosis. However, this antibody also appears in other conditions. By screening antinuclear antibody tests using HEp-2 cells as substrate, 39 patients were shown to have the anticentromere antibody. These patients were divided into 4 groups: group 1 = 17 patients with systemic sclerosis; group 2 = 9 patients with Raynaud's phenomenon alone; group 3 = 7 patients with other connective-tissue diseases, and group 4 = 6 patients with conditions other than those present in groups 1-3. Follow-up over years revealed that some patients suffering solely from Raynaud's phenomenon (group 2) developed the symptoms of systemic sclerosis. In contrast, of the patients who did not have Raynaud's phenomenon (group 4), none developed any symptom suggesting systemic sclerosis. We suggest that the simultaneous presence of Raynaud's phenomenon and the anticentromere antibody predicts the occurrence of systemic sclerosis. In contrast, the presence of the anticentromere antibody alone cannot necessarily be used to predict the development of systemic sclerosis.     

Two cases of gigantic dystrophic calcinosis cutis caused by subcutaneous and/or intramuscular injections.

We describe two female patients with gigantic dystrophic calcinosis cutis caused by a large number of subcutaneous and/or intramuscular injections which they received when they were much younger. Laboratory data and physical examinations were generally within normal limits, and we detected no disease which might induce cutaneous calcification. There are many reports of dystrophic calcinosis cutis caused by injection of several kinds of drugs. However, we found no previous report describing a patient with calcinosis cutis induced by local tissue injury from a large number of injections and with extraordinarily widespread calcification at the injection sites. Because we do not know the exact drugs injected, it is difficult to say if a specific ingredient in the injections was related to this condition. We do know that a large number of subcutaneous or intramuscular injections were frequently administered to patients who had difficulty in maintaining venous infusions in the past, so there may be similar cases of dystrophic calcinosis cutis which have not been reported.     

Case of dystrophic calcinosis cutis in epidermal cyst arising from verrucous epidermal nevus

Dystrophic calcinosis cutis is diagnosed when calcium is deposited into previously damaged tissue by connective tissue disease, panniculitis, pseudoxanthoma elasticum or trauma. We report a case of dystrophic calcinosis cutis arising from the lesion of an epidermal cyst on the verrucous epidermal nevus. A 20‐year‐old woman presented with a polypoid pinkish tumor on a brownish, verrucous plaque. Histopathological findings of the pinkish tumor showed calcium deposits as amorphous, basophilic material lining the true epidermis in the upper dermis, which were compatible with dystrophic calcinosis cutis and the plaque was diagnosed as a verrucous epidermal nevus.     

Quantification of the nail fold capillary abnormalities in systemic sclerosis and Raynaud's syndrome

Measurements were made of capillary luminal diameters and capillary numbers in four groups: 19 normal controls 10 patients with 'idiopathic' Raynaud's disease, 12 patients with Raynaud's phenomenon with an underlying connective tissue disease other than systemic sclerosis, and 18 patients with systemic sclerosis. There was a significant reduction of capillary numbers in all three patient groups compared with the normal controls. Both the afferent and efferent luminal diameters were also increased in each patient group. Patients with Raynaud's phenomenon, either on its own or associated with connective tissue disease, gave results intermediate between normal controls and patients with systemic sclerosis. There were no significant correlations between either the reduction in capillary numbers or increase in luminal diameter with disease severity or duration in systemic sclerosis. It is unlikely that capillary microscopy will provide useful prognostic information for an individual patient with systemic sclerosis; its predictive value in Raynaud's disease must await the outcome of long term follow-up studies.     

Mineralization of collagen and elastic fibers in superficial dystrophic cutaneous calcification: an ultrastructural study

The ultrastructural morphology of localized skin calcifications without associated diseases and with normal serum calcium and phosphate ion values is still unknown. In a case of superficial dystrophic calcinosis cutis (DCC), the role of collagen, elastin and ground substance in the process of calcification and the organization of the apatite crystals could be studied by light and electron microscopy despite technical difficulties in sectioning the hard tissue. Ultrastructural investigation revealed the nucleation of calcification being related to collagen and elastic fibers. No intracellular calcification was found. A flower-like arrangement of pleomorphic crystals was found around single collagen fibrils resembling the calcification of collagen seen in bone tissue. The elastic fibers showed a different pattern of calcification compared with other diseases (e.g. pseudoxanthoma elasticum) with known calcification of the elastic fibers. The process of mineralization was initially linked to the microfibrils of the elastic fiber.     

Generalized cutaneous calcinosis and mixed connective tissue disease.

A 49-year-old female patient with a history of fever episodes, muscular weakness, Raynaud's phenomenon, cardiac insufficiency and increasing cutaneous calcinosis over a period of 4 years is reported. Based upon clinical as well as histological and immunological findings, the disease is diagnosed as mixed connective tissue disease with generalized cutaneous calcinosis in an extent yet unpublished, to our knowledge, in this 'overlap syndrome'. The pathogenesis of cutaneous calcinosis is discussed with particular reference to the phenomenon of calciphylaxis, and some therapeutic implications are considered.     

Systemic sclerosis: Current concepts of skin and systemic manifestations

Systemic sclerosis is an uncommon autoimmune connective tissue disease with multiorgan system involvement and significant associated morbidity and mortality. Cutaneous signs and clinical manifestations are of particular importance, as they may be recognized before systemic manifestations, allowing earlier risk stratification into the limited and diffuse cutaneous subtypes, as well as earlier initiation of treatment. Important cutaneous manifestations include Raynaud’s phenomenon, digital ulcers, cutaneous sclerosis, calcinosis cutis, telangiectasias, pruritus, and dyspigmentation. Despite investigation of a wide variety of treatments, no FDA-approved pharmacologic therapies exist for systemic sclerosis, and data from high-quality studies are limited. In the following review, we will discuss skin-directed therapies. Although there is evidence to support specific treatments for Raynaud’s phenomenon, digital ulcers, and cutaneous sclerosis, there are limited rigorous studies evaluating the treatment of other cutaneous signs and clinical manifestations. Additional randomized-controlled trials and large observational studies are necessary to develop future evidence-based treatment options.     

A dystrophic calcinosis cutis case treated with CO2 laser

Abstract

Calcinosis cutis is the deposition of insoluble calcium salts within cutaneous tissue. It may be divided into four major subtypes: dystrophic, metastatic, idiopathic, and iatrogenic. The most common subtype is dystrophic calcinosis cutis. It can occur as a result of local tissue injury. We herein present a child with dystrophic calcinosis cutis developed following trauma and successfully treated with CO₂ laser.     

The clinical significance of periodic acid-Schiff-positive deposits in cuticle-proximal nail fold biopsy specimens

In vivo capillary microscopic findings and proximal nail fold biopsy specimens from 19 patients with various connective tissue diseases, idiopathic Raynaud's phenomenon, and non-connective tissue diseases were studied. Periodic acid-Schiff-positive serous cuticular deposits were not specific to the group of patients with connective tissue disease. Generally, the severity of deposits correlated with the severity of the in vivo capillary microscopic pattern but not with disease severity or duration. The finding of these cuticular deposits may help to identify those patients with idiopathic Raynaud's phenomenon who are at risk to develop a connective tissue disease.     

Diffuse soft tissue calcifications (calcinosis cutis) in a patient with discoid lupus erythematosus

Soft tissue calcification is known to occur in dermatomyositis, systemic scleroderma and CREST syndrome, but rarely in systemic lupus erythematosus (SLE). Diffuse soft tissue calcifications have not been reported in discoid lupus erythematosus (DLE). In a patient with discoid lupus erythematosus, calcinosis cutis developed about 20 years after the onset of the disease. During the follow-up time of 25 years, manifestations suggestive of a systemic disease were observed in our patient. However, no specific diagnosis could be established. The clinical, light and electron microscopic as well as immunohistochemical findings of our patient are reported. On the basis of electron microscopic findings it is suggested that intracellular calcification occurred in this case.     

A giant calcifying pseudocyst seen in a patient with overlap syndrome

A case of female with a large cystic tumor in her infrascapular region is reported. The tumor was 8 cm x 7 cm in size. Histologically, it was a pseudocyst with calcification. The patient showed no abnormal renal functions other than proteinuria. Because she had suffered from overlap syndromes of systemic lupus erythematosus, progressive systemic sclerosis, and suspected dermatomyositis, we diagnosed this a unique case of dystrophic calcinosis. There have been several reports of cases with connective tissue diseases showing subcutaneous calcification, but to our knowledge no such giant calcifying pseudocyst has ever been reported.     

Subcutaneous calcification presenting in a patient with mixed connective tissue disease and cutaneous polyarteritis nodosa

Subcutaneous calcification often occurs in connective tissue diseases, most commonly scleroderma and dermatomyositis, but is rarely found in mixed connective tissue disease (MCTD). Cutaneous polyarteritis nodosa (PAN) is usually a primary skin disorder and although associated with connective tissue disease, has not been reported previously in MCTD. Calcinosis in cutaneous PAN is not a recognized feature. We describe the case of a 37-year-old woman who presented with tender ulcerated subcutaneous nodules on the lower legs consistent with cutaneous PAN, and she also showed features of MCTD with extensive secondary subcutaneous calcification. The use of systemic immunosuppressive treatment has improved the clinical features of PAN and MCTD but treatment of the calcification has proved challenging. No single medical or surgical treatment has been shown to be consistently effective in subcutaneous calcification, but the introduction of diltiazem in our patient has resulted in some improvement.