Collagen Vascular Disorders

Collagen Vascular Disorders

Endogenous Retroviral Sequences in the Pathogenesis of Systemic Autoimmune Disease

Purpose.—By transcribing viral RNA into DNA, retroviruses reverse the normal direction of genetic information. Retrovirus infection is generally associated with immunosuppression and tumor formation. However, experimental studies have shown that it can lead to chronic inflammatory autoimmune-like diseases as well. Though the pathogenesis is unclear, retroviruses may interfere with the biosynthetic programs of cells and code for proteins that disrupt various cellular functions. Endogenous retroviral sequences (ERVs) are genomic sequences comprising at least 1% of total genomic DNA. Because they are homologous to retroviruses, ERVs can be regulated by similar mechanisms, and thereby mimic the characteristics of exogenous retroviral infection. Evidence on the possible role of ERVs in systemic autoimmune disease is reviewed.

Collagen Vascular Disorders

ERVs in Systemic Autoimmune Disease.—The experimental evidence suggests 2 possible mechanisms whereby ERVs could lead to autoimmune disease. These are expression of ERV gene products with the same antigenic determinants as cellular proteins and activation or destruction of cellular genes resulting from insertional mutagenesis. Though ERV expression can occur under physiologic conditions, it can also lead to production of proteins with epitopes identical to self-molecules. Acting through antigenic or functional molecular mimicry, such autoantigens can lead to breakdown of tolerance. Identical epitopes of self- and non-self proteins may be sufficient to cause reactivity against self molecules. If the structural similarity is great enough to mimic a function of the host’s proteins, functional molecular mimicry can happen as well.

Research is attempting to clarify the role of ERVs in human autoimmune disease. Once ERVs have been characterized in affected patients and healthy controls, functional involvement in gene regulation can be assessed. In vitro cell cultures and in-vivo phototest procedures can be used to study the induction of a local inflammatory reaction by UV radiation in patients with systemic lupus erythematosus; this is one approach to investigating the pathogenetic role of ERVs in a human autoimmune disease. In the in vitro studies, only distinctive members of ERV families are induced by UV radiation. Studies of the relationships between ERVs in class II and class in genes of the MHC and cutaneous and systemic lupus suggest ERV sequences of varying lengths can be identified.

Discussion.—There is evidence to suggest that ERVs could play a pathogenetic role in human systemic autoimmune disease. Potential mechanisms have been identified, and promising research approaches are being pursued.

► This study reviews the potential role that retroviruses may play in the development of chronic inflammatory autoimmune diseases. The mechanisms proposed include disregulation of normal cellular genes through retroviral insertion, and/or expression of antigenic determinants that overlap the viral and host genome. As one example, this would include such illnesses as systemic sclerosis, with expression of cross-reactive epitopes of topoisomerase I and Moloney murine leukemia virus.

Prolidase Deficiency and Systemic Lupus Erythematosus

Background.—Patients with prolidase deficiency, a rare autosomal recessive disorder,, lack the normal ability to recycle proline, causing characteristic iminopeptiduria. The symptoms vary but may include rashes or skin ulcers, dysmorphic features, cognitive impairment, anemia, spleno-megaly, and recurrent infections. Leukocyte, erythrocyte, or fibroblast assays are done to confirm the diagnosis. The authors have previously reported 2 patients with prolidase deficiency who had impaired immune function, characterized by high serum immunoglobulin concentrations. A case of systemic lupus erythematosus (SLE) in a patient with prolidase deficiency was recently reported, but the link between the 2 disorders was unclear. Two authors report 2 additional patients with prolidase deficiency who had SLE diagnosed were reported.

Patients.—The first patient was a boy, the son of first cousins, who received a diagnosis of prolidase deficiency at age 9 months of age. His clinical features included frequent gastrointestinal and chest infections, moderate learning difficulties, and facial dysmorphism. After 7 years of age, he had repeated bacterial infections of the right lung. At 8 years of age, he was hospitalized with abdominal pain, subsequently having a facial abscess, septicemia requiring ventilatory support, a vasculitic rash, thrombocytopenia, neutropenia, proteinuria, pericarditis, and ankle and elbow swelling. The clinical and laboratory findings led to the diagnosis of SLE. The patient died within 4 weeks, despite intensive care, plasmapheresis, and high-dose steroids.

The patient had a cousin, a 5-year-old girl, who also had prolidase deficiency. Her findings included recurrent pyrexial illness with pneumonia, recurrent mouth ulcers, neutropenia, thrombocytopenia, and a florid facial rash in a butterfly distribution. The experience with the first patient led to further investigations, which confirmed the diagnosis of SLE. The patient was effectively treated with oral prednisolone, although she continued to have an elevated erythrocyte sedimentation rate and facial rash.

Discussion.—Prolidase deficiency and SLE are both disturbances of immune function that may have some common clinical features. Prolidase deficiency is probably a risk factor for SLE; this association could help in unraveling the cause of SLE. In addition, some patients with SLE may have prolidase deficiency. This condition may go unrecognized because standard laboratory tests do not detect iminopeptiduria. Specific tests for prolidase deficiency may be indicated in SLE patients with a family history or presentation in childhood.

► Although an enzyme defect most certainly is a factor in only a very small minority of patients with SLE, the identification of such a cause will likely lead to better and more specific treatments for this subset of cases. The era of gene therapy has arrived!

Markers in Cutaneous Lupus Erythematosus Indicating Systemic Involvement: A Multicenter Study on 296 Patients

Introduction.—Lupus erythematosus (LE) has 3 major variants: chronic discoid LE (CDLE), subacute cutaneous LE (SCLE), and systemic LE (SLE). About 5% to 10% of patients with CDLE may experience transition to SLE during the disease course. Systemic involvement may develop in up to 50% to 60% of patients with SCLE. The significance of clinical and laboratory criteria that could act as markers for early recognition of systemic involvement in cutaneous LE was assessed.

Methods.—Between 1989 and 1994, 379 patients with LE seen in 5 cooperating departments of dermatology in Germany and Austria were studied. Of this cohort, 245 had CDLE or SCLE and 51 had SLE. Forty-nine patients with incomplete documentation were not evaluated, nor were 34 patients with other LE subsets. Seven variables were analyzed for value in distinguishing between the CDLE/SCLE and SLE groups: erythrocyte sedimentation rate, titers for antinuclear antibody (ANA), anti- dsDNA-antibodies, photosensitivity, presence of arthralgias, recurrent headaches, and signs of nephropathy.

Results.—The variable with the highest statistical relevance for distinguishing systemic involvement was signs of nephropathy (proteinuria, hematuria). The next most significant variables were presence of arthralgias and high ANA titers (1:320 greater). Low ANA titers and anti-dsDNA antibodies had little or no relevance as criteria for distinction.

Conclusion.—Patients with CDLE with signs of nephropathy, presence of arthralgias, and elevated ANA titers (1:320 or greater) should be followed closely as they may be at risk for systemic LE involvement.

► In a multicenter study, Tebbe et al. evaluated the ability of 7 variables (sedimentation rate, ANA titer, anti-dsDNA-autoantibodies, photosensitivity, presence of arthralgias, recurrent headaches, and signs of nephropathy [proteinuria, hematuria]) to distinguish cutaneous lupus from SLE. Signs of nephropathy, arthralgias, and ANA titers greater than 1:320 were markers for patients fitting the criteria for SLE established by the American Rheumatism Association. Conversely, anti-dsDNA antibodies and low titer ANA failed to distinguish between localized skin disease and systemic involvement.

Disaccharide Analysis of Skin Glycosaminoglycan in Localized Scleroderma

Introduction.—Localized scleroderma, a fibrotic disease of unknown etiology, is characterized by collagen deposition. Skin biopsies from 5 affected patients were examined for changes in skin glycosaminoglycan (GAG). An increased amount of dermatan sulfate (DS) or chondroitin sulfate (ChS) has been identified in skin GAGs of patients with systemic sclerosis (SSc), a disease in which collagen deposition is found on both skin and internal organs, but little is known of altered metabolism of skin GAGs in localized scleroderma.

Methods.—Patients were 4 women and 1 man with an average age of 46 years. All had a diagnosis of morphea, a plaque type of localized scleroderma. Punch biopsy specimens were taken from the central part of the sclerotic lesion and from clinically uninvolved adjacent skin. Also examined were site-matched skin samples from 10 normal controls. Analyses were conducted with a sensitive method of high-performance liquid chromatography after l-phenyl-3-methyl-5-pyrasolone labeling.

Results.—All involved skin exhibited increased amounts of ΔDi-6S, ΔDi-4S(ChS), ΔDi-4S(DS) (the main disaccharide unit of DS) and of the ratio of ΔDi-4S(DS)/ΔDi-HA or dry skin weight. The amount of ΔDi-HA (the main disaccharide unit of hyaluronic acid) and total disaccharide units per 1 mg dry weight were decreased in localized scleroderma sites compared with uninvolved or control skin.

Discussion.—Previous studies have reported increased amounts of GAG, ΔDi-4S(DS), ΔDi-6S, the elevated ratio DS/HA, or a decreased amount of ΔDi-HA in SSc skin or fibroblasts. Together with the present findings, this may suggest a significance for ΔDi-4S(DS) and ΔDi-HA in the sclerotic skin changes of systemic and localized scleroderma. Similar changes, however, occur in keloids or wound healing. The relationship between findings in localized scleroderma and those in SSc suggest that the change in GAG may be closely related to the fibrotic process.

► The authors demonstrate an altered pattern of expression of glycosaminoglycans in localized scleroderma. There were increased amounts of dermatan sulfate and decreased amounts of hyaluronic acid. These findings suggest abnormal fibroblast glycosaminoglycan metabolism in this disease. This may also serve as a useful histologic marker, because dermatan sulfate and hyaluronic acid can be demonstrated by special stains.

The Epidemiology of Morphea (Localized Scleroderma) in Olmsted County 1960-1993

Introduction.—Morphea is a collection of cutaneous disorders characterized by thickening and induration of the skin and subcutaneous tissue without significant internal organ involvement. Homogenization of collagen bundles and reduction in the number or size of dermal appendages are the typical histologic characteristics. Morphea has been categorized into 5 distinct groups: plaque, generalized, bullous, linear, and deep. Little is known about the incidence and prevalence of morphea. A population- based study of morphea and its subtypes was conducted.

Methods.—In a 33-year period, 83 patients (59 female, 23 male) had morphea diagnosed. The clinical manifestations, survival rates, prevalence, incidence, and long-term outcome of these patients were determined. There was a total of 754 person-years of observation.

Results.—The annual age and sex-adjusted incidence was 2.7 per 100,000 population. During the 33 years, the incidence rate increased an average of 3.6% per year. There was a 2 per 1,000 prevalence at 80 years of age. By 3.8 years’ duration, 50% of patients had cutaneous softening or evidence of disease resolution. The plaque group had the shortest active disease duration, with 50% resolution or skin softening by 2.7 years, and the deep group had an active disease duration of 5.5 years. In the linear and deep categories, arthralgias, synovitis, uveitis, and joint contractures were more frequent. Some disease-related disability during the follow-up period occurred in 9 patients (11%), and in the deep group this was common (44%). Severe internal involvement did not occur in any of the patients with morphea. Systemic sclerosis did not develop in any of the patients. The survival rate was similar to that of the general population.

Conclusions.—More common than previously recognized, morphea and its subtypes can lead to important disability.

► This retrospective study from Olmsted County, Minnesota, provides wonderful epidemiologic information about morphea in a defined population spanning a 33-year period- This group has a higher incidence of morphea than might have been expected, and the reason for this remains unclear. What we learn from this article is that in this population, as in others previously reported, morphea tends to be a relatively benign condition limited to the skin. The authors do highlight other associated symptoms and problems including arthralgias, synovitis, and joint contractures. In addition, they identify disability in a small number of individuals, particularly those with widespread or deep morphea. This study confirms the extremely low incidence of progression to systemic sclerosis in this population of patients. Unfortunately, as an epidemiologic study, there is only brief mention of treatments used. It would be useful to go back to this same population and look at the treatment issue a bit more closely, and attempt to correlate treatments used with the course of the disease. In addition, it must be remembered that this group of people from Minnesota is almost entirely white, and there is, therefore, little ethnic diversity. It is thus impossible to state whether these findings can be generalized to larger populations.

Racial Differences in Scleroderma Among Women in Michigan

Objective.—Previous studies have suggested that the incidence, mortality, case fatality, and manifestations of scleroderma differ for black and white women. However, there have been insufficient numbers of women of both races to confirm these differences. Racial differences in scleroderma were analyzed as part of a large, population-based, case-control study.

Methods.—Five different sources were used in an attempt to identify all women in the state of Michigan with a diagnosis of scleroderma from 1980 through 1991. The study was designed to identify possible risk factors for scleroderma. Seventy-four different clinical and laboratory variables were derived from the patients’ medical records, together with demographic and follow-up data. This information was used to assess possible racial differences in scleroderma, including age at diagnosis, extent of disease, clinical manifestations, disease incidence, and survival.

Results.—Of 514 women with scleroderma identified, 23% were black and 77% were white. The mean age at diagnosis was 44.5 years in black women vs. 51.5 years in white women. The black women had earlier onset of both diffuse and limited disease, although these estimates were not adjusted for population frequencies. Fifty percent of black patients had diffuse scleroderma, compared with 25% of white patients. The estimated incidence of scleroderma was 14.1/million/year overall: 22.5/million/year for black women, and 12.8/million/year for white women. The higher incidence of scleroderma among black women was particularly notable before the age of 54 years. Black women of all ages were more likely to have diffuse scleroderma. Patients with diffuse scleroderma were more likely to have pericarditis, pleural effusions, myositis or myopathy, renal insufficiency, and a history of hypertensive crisis. Complications occurring more frequently in black patients were pericarditis, pulmonary hypertension, pleural effusions, myositis/myopathy, and renal insufficiency. Women with limited scleroderma were more likely to have anticentromere anti-bodies, but the frequencies of antitopoisomerase I antibodies were similar between disease groups. Survival at 7 years after diagnosis was 76.5% overall, 72.5% for black women, and 77.6% for white women.

Conclusion.—Important racial differences in scleroderma are indicated in this large study. Black women with scleroderma are more likely to have diffuse disease, be at a younger age at diagnosis, and have signs of aggressive disease. After adjustment for age at diagnosis, these women have a worse prognosis as well. Regardless of race, survival of patients with scleroderma is negatively affected by internal organ involvement and diffuse disease. The higher incidence of scleroderma among black women is almost entirely accounted for by their higher rate of diffuse disease.

► In this population, scleroderma appeared to be of earlier onset and more severe in black women than in white women. It is important to monitor all patients with diffuse scleroderma for the possibility of systemic involvement.

Nailfold Capillary Abnormality and Pulmonary Hypertension in Systemic Sclerosis

Introduction.—In a previous study the authors report a correlation between nailfold capillary, abnormality and peripheral microvascular abnormalities in patients with systemic sclerosis (SSc). The present study of 44 patients with SSc and 40 normal controls examines the correlation between cardiopulmonary findings, including pulmonary arterial pressure, and nailfold capillary abnormalities.

Methods.—The randomly enrolled patients with SSc had a mean age of 50.3 and a mean duration of disease of 11.1 years; the male/female ratio was 6/38. Controls were matched with patients with SSC for age, sex, and race. Nailfold capillaries were examined by capillary microscopy, and pulmonary arterial pressure was measured with right-heart catheterization.

Results.—Canonical discriminant analysis using 4 parameters measured by capillary microscopy revealed that all parameters of patients with SSc showed significantly higher values than those of normal controls. Overall, 32 of 44 patients with SSc exhibited an abnormal SSc-type capillary pattern. A normal capillary pattern was found in 12 patients and in all controls. There was a significant correlation between the SSc pattern and elevated pulmonary vascular resistance, pulmonary fibrosis, electrocardio-graphic abnormalities, decreased vital capacity, and decreased diffusion capacity for carbon monoxide (DCCM). The SS pattern was present in all patients with pulmonary hypertension, and the highest rate of abnormalities among these patients was seen in conjunction with elevated capillary microscopy and DCCM. A limited-type SSc was significantly correlated with DCCM and anticentromere antibody, whereas the diffuse-type SSc correlated with pulmonary fibrosis and anti-scl-70 antibody.

Conclusion.—Nailfold capillary abnormalities in patients with SSc were found to be closely related to pulmonary arterial hypertension. Decreased DCCM was seen with greater frequency in the limited-type SSc, and pulmonary fibrosis occurred in the diffuse-type SSc.

► The authors demonstrate the clinical utility of nailfold capillary microscopy. They show a positive predictive value for the clinical finding of nailfold capillary abnormality in patients with systemic sclerosis; i.e., all systemic sclerosis patients with pulmonary hypertension had abnormal nailfold capillaries. Nailfold capillary loops were also significantly altered in patients with pulmonary fibrosis and anti-scl-70 antibodies. As such, this clinical finding may serve to identify patients at risk for higher mortality.

Type 2 Helper T-cell Predominance and High CD30 Expression in Systemic Sclerosis

Introduction.—In patients with progressive systemic sclerosis (SSc), CD4+ T cells are the main subpopulation, although CD8+ cells are present as well. Many different cytokines with the capability to alter endothelial cell function have been identified in sera or tissues from patients with SSc. Studies have shown that CD4+ helper T cells—Th cells— can release cytokines and are associated with differing patterns of immunologic reaction. Skin-infiltrating T cells from patients with progressive SSc were studied to determine their pattern of cytokine production.

Methods and Findings.—Of 97 T-cell clones generated from the skin of patients with SSc, 96 were CD4+. In contrast, of 153 clones generation from the skin of patients with atopic dermatitis, 117 were CD4+ and 36 were CD8+. Most CD4+ T-cell clones from patients with SSc produced interleukin-4 (IL-4) but not interferon-γ (IFN-8), in a restricted Th2-like profile. By comparison, most CD4+ clones from patients with atopic dermatitis produced both IFN-γ and IL-4, which is a Th0-like profile, although some had a Th1-like profile and others had a Th2-like profile. Most patients with SSc showed high levels of soluble CD30, including almost all patients with diffuse SSc.

Conclusions.—The findings suggest a Th2-like pattern of cytokine gene expression and cytokine production in patients with SSc. The high levels of soluble CD30 expression are consistent with the predominant activation of Th2 cells in SSc. Predominant activation of Th2-like T cells may offer new insights into the pathophysiology of SSc. However, it remains to be seen whether the cytokine changes occur before or after Th2-cell activation.

► Mavilia et al. have strikingly demonstrated that T-cell clones generated from patients with SSc uniformly exhibit a type 2 helper cell (Th2) cytokine profile. This T-cell subset, which is capable of producing IL-4 but not IFN-8, also expresses CD30, a member of the tumor necrosis factor-receptor superfamily. The level of soluble CD30 in the serum correlates with the extent of disease. The data presented here suggest that the pathogenesis of SSc may involve production of IL-4. This could lead to collapse of vimentin intermediate filaments around the nucleus of endothelial cells, which in turn might allow migration of T cells into the skin, resulting in inflammation and fibrosis. The source of IL-4 is unclear, as is whether the Th2 overexpression is driven by defects in the production of certain cytokines (such as IFN-α/γ and IL-12 ).

Psoralen UVA Therapy for Linear and Generalized Morphea

Purpose.—Although spontaneous remission of linear and generalized morphea is possible, patients may experience considerable morbidity. Al-though many different treatments have been tried, the results have been disappointing. Other inflammatory dermatoses have been successfully treated with oral psoralen A plus ultraviolet A (PUVA) photochemotherapy. An experience with PUVA therapy in patients with linear or generalized morphea is reported.

Patients.—The experience included 2 patients with linear morphea and 2 with generalized morphea. Each patient’s earliest lesions were atrophic, whereas the more recent lesions were erythematous, with no significant epidermal change. All patients had progressive disease, with new lesions appearing within the previous month. Each patient received a course of PUVA therapy. This consisted of oral methoxsalen (Oxsoralen Ultra, 0.4 mg/kg) followed by UVA exposure of the affected areas. The patients received 3 UVA treatments per week.

Outcomes.—In the 2 patients with generalized morphea, the erythematous lesions cleared. This left behind hyperpigmented skin, which gradually faded . One of the patients with linear morphea had hyperpigmentation which was replaced by relative hypopigmentation during treatment and, eventually, by normal-colored skin. There was no change in areas that were atrophic and scarred before treatment, except for loss of induration.

Discussion.—This experience suggests that oral PUVA therapy can halt the progression of linear and generalized morphea while reversing the inflammatory changes. This therapy leads to clearing of the most recent lesions, although it does not reverse scarring and atrophy. Thus starring PUVA treatment as soon as possible will help minimize residual deformity in patients with morphea.

► Narrow band UVA and oral calcitriol are two other “alternative” treatments that recently have been proposed for morphea.

Correlations Between Change in Disease Activity and Changes in Peripheral Blood Lymphocyte Subsets in Patients With Juvenile Dermatomyositis

Introduction.—No single test has proved a reliable indicator of disease activity in patients with juvenile dermatomyositis (JDM). Several abnor-malities in peripheral blood lymphocytes have been identified in patients with new onset, untreated JDM. Increases in the proportion of B cells have been observed in adults with dermatomyositis and a child with JDM. Changes in lymphocyte subsets were evaluated to determine whether they correlated with disease activity in children with JDM.

Methods.—Twenty-three children with JDM were evaluated for disease activity score (DAS) and underwent flow cytometric analysis to analyze peripheral blood lymphocyte subsets at 2 specific time intervals.

Results.—Changes in percentage of peripheral B cells were significantly correlated with changes in disease activity, with increased percentages indicating active disease. There were no significant associations between changes in CD4 positive T-helper cells, CD8 positive T-suppressor cells, or changes in CD3 + cells expressing the activation markers CD25 or HLA- DR. There was a direct correlation between improvement or worsening of DAS and variations in the percentage of peripheral blood B cells. Anti- nuclear antibody was present in 60% of these children and increases in serum IgG and expression of B-cell activation markers were also observed.

Conclusion.—There was a correlation between change in DAS and the percentage of peripheral blood B cells in patients with JDM. This finding may be useful as an indicator of immunologic activity and response to therapy.

► Markers for disease activity in JDM include creative phosphokinase and aldolase, von Willebrand’s factor antigen, and neopterin. Eisenstein et al. have demonstrated that the percentage of peripheral blood CD19+ lymphocytes (B cells) also reflects disease activity. No correlation was found between the presence of CD4+ T-helper cells, CD8+ T-suppressor cells, or CD3+ lymphocytes expressing activation markers CD25 or HLA-DR. From a clinical standpoint, such work is important as no single laboratory marker appears to be an adequate marker of disease activity.

Low-dose Methotrexate Administered Weekly is an Effective Corticosteroid-sparing Agent for the Treatment of the Cutaneous Manifestations of Dermatomyositis

Objective.—Methotrexate, an irreversible inhibitor of dihydrofolate reductase, is effective for treating the muscle involvement in dermatomyositis. Results of low-dose weekly methotrexate treatment of resistant cutaneous disease in 13 patients with dermatomyositis is discussed.

Methods.—Thirteen patients, age 18-77 years, with cutaneous disease unresponsive to other therapies including chloroquine, hydroxychloroquine, quinacrine, prednisone, and azathioprine, were treated with weekly doses of methotrexate ranging from 2.5 to 30 mg for 3-31 months.

Results.—Four patients were clear, 4 were nearly clear, and 5 improved moderately. A steroid-sparing effect was apparent in 10 patients taking prednisone concurrently.

Conclusion.—Methotrexate was a safe and effective steroid-sparing therapy for treatment of resistant cutaneous disease associated with dermatomyositis.

► Methotrexate alone or in combination with prednisone can be an effective therapy for the treatment of autoimmune diseases, including collagen vascular diseases and blistering disorders. Obviously, the same precautions exercised in monitoring methotrexate-treated patients with severe psoriasis must be practiced in these individuals as well.

Calcinosis Universalis Complicating Juvenile Dermatomyositis: Resolution During Probenecid Therapy

Background.—As many as half of patients with juvenile dermatomyositis (JDM) may have ectopic calcification. This can be a debilitating complication, associated with pain, skin ulcers, muscle atrophy, joint contracture, and acro-osteolysis. Some cases of spontaneous regression have been reported. There is no accepted treatment once calcification has occurred, although surgery may be performed for extensively calcified areas. A patient with, ectopic calcifications that resolved during treatment with probenecid was described.

Case.—Man, 18, was evaluated for diffuse, progressive periarticular calcifications as a complication of JDM. He had a 4-year history of progressive subcutaneous calcifications, despite phosphate-binding antacid therapy [A1(OH)3]. Motion of his shoulders and hips was significantly limited by calcifications. The patient was placed on a restricted calcium and phosphorus diet, with continued A1(OH)3 therapy. Six months later, he was started on a trial of oral probenecid, gradually increasing the dosage from 250 mg/day to 500 mg 3 times daily. Within 3 months, the patient reported reduced pain. By 7 months, he had dramatic improvement of calcifications on both physical and radiographic examination. The patient’s well-being and range of motion improved substantially.There were no complications related to probenecid therapy. His blood phosphate level decreased, apparently as a result of probenecid therapy rather than the low-phosphate diet.

Discussion.—This patient with extensive ectopic calcifications complicating JDM responded to treatment with probenecid. In this case, a renal- mediated reduction in blood phosphate levels appears to have reequili-brated complexed mineral phosphate with extracellular inorganic phosphate, leading to dissociation of the ectopic calcium. With continued phosphaturia, the ectopic calcifications progressively decreased. However, more detailed studies of mineral homeostasis will be needed to confirm the efficacy of probenecid in patients with ectopic calcification and to determine its mechanism of action.

► Other treatments that have been proposed for calcinosis cutis associated with collagen vascular diseases have included warfarin, colchicine, bisphosphonates, phosphate-binding antacids, intralesional corticosteroid injections, and diltiazem, a calcium ion influx inhibitor.

Atypical Lymphoid Infiltrates Arising in Cutaneous Lesions of Connective Tissue Disease

Introduction.—Patients with various connective tissue diseases (CTDs) sometimes exhibit atypical lymphoid infiltrates (ALIs). Most of these are B-cell neoplasms, although some are T-cell lymphomas and leukemias. Preneoplastic immunoproliferative lesions can also occur. Seventeen patients with ALIs arising within cutaneous lesions of their CTDs were described.

Patients.—Seventeen patients with a confirmed or suspected CTD syndrome whose skin biopsy specimens included features of CTD along with lymphoid atypia were studied. Fifteen patients had cutaneous lesions of CTD with pseudolymphomatous features, whereas the other 2 had malignant T-cell lymphomas arising in CTD lesions.

Findings.—The pseudolymphomatous infiltrates fell into 4 morphologic categories. One was a lymphomatoid vascular reaction/lymphomatoid vasculitis, associated with a pleomorphic lymphohistiocytic infiltrate with prominent histiocytes and unusual serpentine nuclei. In the second pattern, there was a dense, atypical epidermotropic or folliculotropic T-cell-rich lymphocytic infiltrate, mimicking cutaneous T-cell lymphoma . Some cases showed a lymphocytoma cutis pattern, distinguished by a nodular small, mature lymphocytic infiltrate with little or no lymphoid atypia. The fourth pattern, which looked like subcutaneous T-cell lymphoma, was found in cellular lesions of lupus profundus. The remaining 2 patients had cutaneous T-cell lymphomas arising in cutaneous lesions of CTD.

Conclusions.—Atypical lymphoid infiltrates can occur in cutaneous lesions of CTDs. Most of these lesions are pseudolymphomatous in nature, rather than malignant lymphomas, and the former lesions very rarely progress to the latter. The occurrence of ALIs in cutaneous CTDs is probably related to systemic immune dysregulation.

► The authors conclude that ALIs occurring in cutaneous lesions of CTD usually represent a pseudolymphomatous process rather than a malignant lymphoma. However, if CTD lesions should become resistant to conventional treatment modalities, consideration should be given to the possibility of an evolving T-cell dyscrasia.