The effects of warfarin on calcinosis in a patient with systemic sclerosis

We describe the use of low doses of warfarin to treat calcinosis in a patient with systemic sclerosis or CREST syndrome. Our patient had Raynaud's phenomenon, skin sclerosis of the neck and the distal surface of the elbows, and pitting ulcers and scarification of the fingers as well as cutaneous calcinosis. After beginning warfarin, no calcium containing substance was discharged from the fingertip ulcers. There was no tendency to bleed and activated partial thromboplastin time and prothrombin time were normal. Sequential radiographs of the hands showed that calcinosis had improved. Since there seem to be few adverse effects, the use of warfarin in patients with calcinosis warrants further study.     

Clinical aspects of systemic and localized scleroderma

After the skin, the gastrointestinal tract is the most frequently affected organ in systemic sclerosis. Gastrointestinal symptoms already may be present early in the course of the disease and do not necessarily correlate with objective findings. Esophageal dysmotility is not specific for systemic sclerosis but occurs in other connective tissue diseases as well. Peripheral macrovascular disease was shown to be increased in patients with limited cutaneous sclerosis; signs of autonomic dysfunction were found in patients with the CREST (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) variant. Pulmonary involvement was shown to be moderately or severely decreased in 40% of a large cohort of scleroderma patients. In one study, no support was found for the association between pulmonary involvement and gastroesophageal reflux. Peripheral nerve involvement is often subclinical and might be associated with anti-U1-RNP and anti-topoisomerase I antibodies. Internal organs are seldomly affected in localized scleroderma. When occurring in childhood and involving an extremity, localized scleroderma can cause growth failure, resulting in long-term functional disability.     

Large vessel occlusive disease associated with CREST syndrome and scleroderma

OBJECTIVES: To report the cases of three patients with CREST syndrome and one patient with diffuse scleroderma who had severe macrovascular disease and only minimal vascular risk factors. METHODS: The medical histories, physical examinations, and results of clinical investigations were reviewed in four patients. RESULTS: These four patients had severe morbidity from macrovascular disease of the arms and legs in the presence of minimal underlying vascular risk factors. These patients represent 11% of the women with scleroderma seen at our hospital since 1974. This is a greater than threefold increase above the expected proportion of symptomatic vascular disease seen in population studies. In the patients with CREST syndrome, large vessel disease was first seen more than 10 years after the onset of Raynaud's phenomenon, which was the first manifestation of the disease. A pathological specimen of the ulnar artery from one patient showed severe luminal narrowing by an acellular material with no evidence of atheroma. CONCLUSIONS: These cases suggest an association of both the CREST syndrome and scleroderma with macrovascular disease.     

Silicone-reactive disorder: a new autoimmune disease caused by immunostimulation and superantigens

Over 100 cases of disorders closely resembling classic autoimmune diseases have been reported among patients who were injected or implanted with a diverse group of chemicals including paraffins, vegetable oils or silicone. Most cases have occurred in silicone breast implant recipients, especially those who received their prostheses 2-10 years prior to onset of symptoms. A high proportion of patients exhibit classic signs and symptoms of Sjogren's syndrome or scleroderma. Affected patients typically experience some combination of fatigue, myalgia, joint pain, sicca syndrome (dry eyes and mouth), synovitis, rash, alopecia, muscular weakness or lymphadenopathy, and autoantibody formation. Less commonly, patients may have the CREST syndrome (calcinosis, Raynaud's phenomena, esophageal hypomotility, sclerodactyly and telangiectasias), hypertension, pulmonary fibrosis, or central nervous system pathology.     

Six cases positive for anti-centromere antibodies with ulcer and gangrene in the extremities

We report six cases that were positive for anti-centromere antibodies, with ulcer and gangrene in the extremities but mild or no skin thickening. The patients were five women and one man, and the mean age at onset of gangrene was 56 yr. Raynaud's phenomenon was found in five patients and calcinosis cutis in two patients. Three patients did not satisfy the criteria for systemic sclerosis and CREST syndrome in this study. Ulcer and gangrene occurred in the fingers in three patients, and in the fingers and toes in two patients. The gangrene was refractory to treatment, and amputation of fingers or toes was inevitable in five patients. Regardless of cutaneous lesion, the presence of anti-centromere antibodies may cause the same pathological presentation of vascular damage as seen in systemic sclerosis.     

A case-control and nerve biopsy study of CREST multiple mononeuropathy

From 536 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasis), seven were identified as having peripheral neuropathy not attributable to another cause. Peripheral neuropathy developed 0 to 25 years after their first symptoms of scleroderma. Unexplained neuropathy in CREST patients (seven patients) was more frequent than in control subjects (two patients) matched for age, sex, time of evaluation, and geographic referral region. Multiple mononeuropathy occurred significantly more frequently in the CREST group (six patients) than in the control group (0 patients). Four sural nerve biopsy specimens from the CREST patients demonstrated multifocal fiber loss and perivascular inflammation; one was diagnostic for necrotizing vasculitis and two others were highly suggestive for necrotizing vasculitis. The density of myelinated fibers in three nerves from CREST patients was significantly decreased, whereas the index of dispersion (a measure of multifocal fiber loss) was increased, and the frequency of axonal degeneration was significantly increased. Based on these clinical and pathologic findings, we conclude that in the CREST syndrome multiple mononeuropathy, although occurring infrequently, occurs more frequently than by chance and necrotizing vasculitis is the cause of this multiple mononeuropathy.     

Thyrotoxicosis and renal tubular acidosis presenting as hypokalaemic paralysis

We report a case of oesophageal disease as the first manifestation in a patient with CREST syndrome. A 46-year-old man with achalasia-like syndrome developed CREST syndrome 4 years later. A pneumatic dilatation of the cardia was performed. After pneumatic dilatation the dysphagia and regurgitation disappeared but the patient developed reflux oesophagitis. Four years after diagnosis of oesophageal disease he presented with a clinical picture of CREST syndrome. An acute ileus and constipation developed later. After receiving medical therapy with omeprazole and cisapride the patient is free of oesophageal symptoms and bowel movements are normal. Oesophageal disease is common in patients with limited and diffuse scleroderma, but to our knowledge achalasia-like syndrome has not been previously described as the first manifestation of the systemic disease.     

Calcium carbonate apatite deposition in the cervical spine with associated vertebral destruction. Case report

This 52-year-old woman developed crystal deposition disease involving the cervical vertebrae. She presented with symptomatic spinal cord compression secondary to extensive calcified lesions in the posterior elements of the cervical spine. Surgical decompression with posterior fusion was performed. Histological examination showed hardened deposits of calcium carbonate involving the soft tissue, and dissolution of the vertebral bone trabeculae. There was no inflammatory response to these deposits. One year postoperatively the patient developed severe pulmonary disease associated with the collagen-vascular disorder, scleroderma (calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia [CREST] syndrome). Calcium carbonate deposition disease represents an unusual clinical entity that is possibly associated with scleroderma or other collagen-vascular diseases, and it is distinct from ligamentum flavum calcification, calcium pyrophosphate deposition disease, and hydroxyapatite deposition disease.     

Gastrointestinal hemorrhage in patients with systemic sclerosis and CREST syndrome

OBJECTIVES: Systemic sclerosis (SSc) and calcinosis, Raynaud's phenomenon, esophageal disease, sclerodactyly, telangiectasia (CREST) syndrome present distinctive microvasculature lesions that are thought to be responsible for tissue damage and disease progression. Involvement of the gastrointestinal tract may lead to the occurrence of profuse hemorrhage. We performed a study to assess the incidence and characteristics of gastrointestinal hemorrhage in a large group of patients with SSc and CREST syndrome. METHODS: We reviewed the medical records of 144 patients with SSc/CREST seen at our institution during the period 1985-1996. Endoscopic findings and clinical data were correlated. Data are expressed as means +/- SD. RESULTS: Twenty-two of 144 (15.2%) patients had at least one episode of gastrointestinal hemorrhage (16 women, 6 men; mean age, 59.4 +/- 17.6 yr). Eight patients (8/22; 36%) had multiple episodes and four (4/22; 18%) required chronic transfusion therapy. Mucosal telangiectasias were the most common cause of bleeding (9/22; 40.9%), followed by peptic ulcer disease (7/22; 31.8%) and erosive gastritis (3/22; 13.6%). Bleeding telangiectasias occurred in the entire gastrointestinal tract, including oral cavity (n = 1), esophagus (n = 1), stomach (n = 3), duodenum (n = 1), ileum (n = 1), cecum (n = 2), and colon (n = 2). Mortality was 22.7% in patients with gastrointestinal bleeding, compared with 7.3% in patients without bleeding. CONCLUSIONS: Patients with SSc/CREST syndrome are at risk of developing severe gastrointestinal hemorrhage. This complication is associated with frequent hospitalization, blood transfusions, and increased mortality. Mucosal telangiectasias are the most common source of bleeding. Appropriate endoscopic intervention is recommended in evaluating and preventing bleeding in patients with SSc/CREST.     

Anticentromere antibodies in rheumatologic practice are not consistently associated with scleroderma

Anticentromere antibodies identified by indirect immunofluorescence are a valuable aid to the diagnosis and prognosis of patients with systemic sclerosis since they are associated in 50% to 80% of cases with limited cutaneous systemic sclerosis, a pattern usually associated with a good prognosis. We studied clinical presentations in rheumatology patients with anticentromere antibodies by indirect immunofluoresence and by ELISA and/or Western blot, but without scleroderma or Raynaud's phenomenon. Eight of 34 (23.5%) rheumatology clinic patients with centromere antibodies met these criteria, seven women and one man, with a median symptom duration of six years (range 1-20 years). Four had Sj?gren's syndrome, one had isolated xerostomia, one systemic lupus erythematosus, one seronegative symmetric polyarthritis and one primary biliary cirrhosis with arthralgia. The mean anticentromere antibody titer in these eight patients was similar to that in the patients who had at least Raynaud's phenomenon. Given the low incidence of scleroderma, these data illustrate the poor predictive value of anticentromere antibodies for the diagnosis of scleroderma in rheumatology clinic patients.     

Laparoscopic Anderson-Hynes pyeloplasty in children

A 49-year-old Japanese woman had been suffering from limited cutaneous scleroderma with papular mucinosis. Papular mucinosis was characterized by multiple, asymptomatic, elevated, skin-colored papules on the dorsal regions of the hands. Histopathological findings of the hard papules showed a marked deposition of hyaluronic acid along sclerosis in the middle and the lower parts of dermis. Serological studies revealed a positive antinuclear antibody (speckled type). Intravenous administration of prostaglandin E1 derivatives reduced the size of the papules, the degree of sclerodactyly and the severity of her Raynaud's phenomenon. These observations suggest that manifestations of scleroderma could be found in some cases of papular mucinosis.     

Osteochondral lesions of the proximal phalanx of the great toe: a report of two cases

OBJECTIVE: To establish whether diltiazem reduces subcutaneous calcinosis (SCC) in patients with systemic sclerosis (SSc), and whether this calcinosis is related to other signs or symptoms. METHODS: 47 patients with SSc were evaluated and divided into two groups according to the presence or absence of SCC. RESULTS: Among the 12 patients with SCC who were treated with diltiazem and had sequential hand radiographs (differential time between the two radiographs: 7.8+/-4 years), there was a slight radiological improvement in three patients only. More patients with SCC had anticentromere antibodies than patients without (p = 0.003), fewer had anti-Scl 70 antibodies (p = 0.01), more had telangiectasia and giant capillaries ( p + 0.04 and 0.048 respectively), and SCC patients had significantly fewer capillaries at the nailfold (p = 0.03). CONCLUSION: These results do not clearly indicate that diltiazem is effective in calcinosis associated with SSc. Among the patients with SSc, those who also had SCC exhibited a distinctive autoimmune profile and more severe cutaneous capillary injury than those without SCC.     

Association of amyotrophic lateral sclerosis with scleroderma. Study of 2 cases

We report a clinical association of diffuse scleroderma and amyotrophic lateral sclerosis (ALS) in two patients. Scleroderma was diagnosed on skin, digestive, osteoarticular, pulmonary lesions and inflammatory syndrome. ALS was suspected on the association of diffuse amyotrophy, fasciculations, pyramidal tract involvement and electrophysiological data. Chronic medulla ischemia and or immune abnormalities are proposed as potential pathological mechanisms for ALS but fortuitous association can not be excluded.     

CT angiogram sign: incidence and significance in lobar consolidations evaluated by contrast-enhanced CT

BACKGROUND: Neuropathological data are very scarce in systemic sclerosis and fail to demonstrate primary changes in the brains of such patients. CASE DESCRIPTIONS: A 41-year-old woman with CREST syndrome developed signs of dementia after an episode of severe dehydration and died two months later of septic shock. A 63-year-old woman with CREST syndrome and a history of two unexplained transient ischemic attacks had had balance disorders since age 62. She died of severe pulmonary hypertension. In both cases, the autopsy showed extensive wall calcification of small arteries and arterioles in the brain, primarily in the basal ganglia, and also in the frontal lobes and the cerebellar area in the second case. No known cause of cerebrovascular calcification was found in either patient. CONCLUSION: The neuropathological findings in these two patients suggest that systemic sclerosis may induce primary vascular changes in the brain, of which calcification may be a marker.     

The concurrence of rheumatoid arthritis and limited systemic sclerosis: clinical and serologic characteristics of an overlap syndrome

OBJECTIVE: The characteristics of 3 patients with longstanding rheumatoid arthritis (RA) and consecutive evolution of limited cutaneous systemic sclerosis (IcSSc) were evaluated and compared with those of patients with IcSSc alone (n = 20) or with RA alone (n = 120). METHODS: Clinical features of the different patient populations were compared. Serologic analyses included tests for antinuclear antibodies (ANA) and ANA subsets, in particular anticentromere antibodies (ACA) and anti-heterogeneous nuclear RNP (hnRNP)-A2/RA33 (anti-A2/RA33). RESULTS: The 3 patients with RA developed IcSSc 11, 29, or 50 years after the onset of RA. Features of IcSSc were Raynaud's phenomenon, sclerodactyly, and telangiactasias in all 3 patients, and esophageal dysmotility in 1 patient. Rheumatoid factor (RF) and anti-A2/ RA33 were each found in 2 patients, and 1 of these patients was seropositive for both RF and anti-A2/RA33. ACA titers were positive in all cases. However, similar to the development of RA prior to IcSSc, the occurrence of autoantibodies typical of RA preceded the occurrence of ACA, at least in 2 of the patients. Using affinity-purified antibodies, cross-reactivities between anti-centromere protein A (CENP-A) and anti-CENP-B antibodies with anti-A2/RA33 antigens were seen in the 2 anti-A2/RA33-positive patients. Such cross-reactivities were not found in IcSSc patients without concomitant RA. Epitope mapping revealed that both autoantibody specificities recognized the known major epitopes: anti-CENP-B reacted with the C-terminal region and anti-A2/RA33 with the second RNA binding domain in the N-terminal region of hnRNP-A2. CONCLUSION: The RA-lcSSc overlap syndrome in these 3 patients with longstanding RA was characterized by an incomplete CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias) syndrome. The study demonstrated the presence of autoantibodies typical of both diseases and cross-reactivity of ACA with hnRNP-A2/RA33 in the sera of these patients.     

Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure

Eleven patients with chronic renal failure and presumed secondary hyperparathyroidism developed a syndrome of medial calcinosis of the arteries and painful ischemic ulcers of the fingers, legs, or thighs, or any combination of the three. Five patients required maintenance hemodialysis; six had functioning renal homografts. Severe hyperphosphatemia had existed in each; seven showed roentgenographic evidence of subperiosteal resorption. Similarities are evident between the lesions and experimentally produced calciphylaxix. The lesions demonstrated a relentless, progressive course, with serious morbidity and mortality. Hyperplastic or adenomatours parathyroid tissue was removed from ten of 11 patients unergoing surgical procedures; healing followed in seven patients. Treatment with phosphate-binding antacids to lower serum phosphorus levels may prevent this syndrome. Total or subtotal parathyroidectomy should be considered when ischemic skin lesions appear in uremic patients or in renal transplant recipients.     

Modulation of delta9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat

We characterized the development of the anti-centromere antibody in a patient prior to the development of CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) symptoms. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by immunoblotting (IgG and IgM) of cellular extracts enriched for centromere antigens and indirect immunofluorescence were used to study the anti-centromere immune response. The sera recognized 3 centromere antigens with molecular masses 18,000 (CENP-A), 50,000 (CENP-D), and 80,000 (CENP-B). For CENP-A, IgM was present before the appearance of the IgG response. Anti-CENP-D revealed an IgM response that decreased over time but no IgG, while CENP-B showed an IgG response that strengthened and then weakened over time. The appearance of an anti-centromere nuclear fluorescence pattern correlated with the appearance of IgG anti-CENP-A. Signs and symptoms typical of CREST began about 4 years after antibodies to centromere antigens were found. The development of the CREST syndrome in our patient was preceded by the appearance of anti-centromere autoantibodies. For at least one of the antigens (CENP-A), there was an immunoglobulin class switch from IgM to IgG.     

Advances in palliative care for the patient with scleroderma

Few studies published within the past year have addressed palliative care for the patient with scleroderma or systemic sclerosis. However, progress continues to be made, and important contributions have been made with respect to different vasodilator preparations for Raynaud's phenomenon, a possible role for diltiazem in the treatment of calcinosis, and the treatment of gut dysmotility. A number of comprehensive review papers on different aspects of management, mainly organ based, were included in the recently published textbook Systemic Sclerosis. Until there is an effective disease-modifying treatment for systemic sclerosis, management will be largely palliative and is best delivered by a multidisciplinary team.     

Echocardiographic diagnosis of single coronary artery in double-outlet right ventricle

A 90-year-old woman was admitted to our hospital in December 1993 because of dyspnea on exertion and malaise. She had been well until October 1993, when she first noticed Raynaud's phenomenon, skin tightening, digital ulceration and scarring of her hands. On physical examination, generalized edema was found, along with acrosclerosis with contracture, especially in the fingers, wrists, and elbows. Inspiratory crackles were noted. A roentgenogram of the chest and an echocardiogram revealed pulmonary fibrosis, pulmonary congestion, and massive pleural and pericardial effusions. The pleural effusion was a transudate. Progressive systemic sclerosis was diagnosed, and furosemide and isosorbide were given. The edema and pulmonary congestion resolved, but the pleural and pericardial effusions did not. Prednisolone was given, which reduced the pleural effusion but not the pericardial effusin. The pleura and the pericardium are not usually involved in progressive systemic sclerosis, and this disease rarely occurs in patients over 70 years old. To the best of our knowledge, this was one of the oldest patients with progressive systemic sclerosis. The combination of massive pleural and pericardial effusions, and the advanced age of onset make the present case unusual.