Effect of chloroquine phosphate treatment on serum MMP-9 and TIMP-1 levels in patients with systemic lupus erythematosus.

Antimalarials are widely used for the treatment of systemic lupus erythematosus. However, their mechanisms of action have not been fully elucidated. Literature data indicate that matrix metalloproteinases may play a role in the immune response and tissue damage that occur in autoimmune skin diseases. The aim of this study was to determine the effect of 3 months of chloroquine treatment on serum levels of MMP-9 and TIMP-1 in patients with systemic lupus erythematosus. The study group consisted of 25 patients with systemic lupus erythematosus and 25 sex- and age-matched healthy volunteers. Before drug administration, serum levels of MMP-9 and TIMP-1 were determined by enzyme-linked immunosorbent assay. The same procedure was performed after chloroquine treatment. We found significantly higher median serum levels of MMP-9 in patients with systemic lupus erythematosus before therapy (57.20 ng/ml) when compared with controls (44.50 ng/ml) (p < 0.001). After chloroquine therapy the median MMP-9 serum level of systemic lupus erythematosus patients decreased significantly (43 ng/ml; p < 0.001). Before treatment the median TIMP-1 serum level in the patients with systemic lupus erythematosus was significantly higher than in the control group (500 vs. 200 ng/ml; p < 0.001), and after therapy it increased significantly (750 ng/ml TIMP-1; p < 0.001). The results suggest that chloroquine treatment may affect the matrix metalloproteinase network, and this effect may contribute to the immunoregulatory and anti-inflammatory properties of antimalarials.

The influence of antimalarial treatment on IL-1beta, IL-6 and TNF-alpha mRNA expression on UVB-irradiated skin in systemic lupus erythematosus.

BACKGROUND: There are very few data addressing the mechanisms of antimalarial treatment benefit locally within the skin of patients with lupus erythematosus, at the level of cytokine messenger RNA (mRNA) expression. OBJECTIVES: The aim of this study was to evaluate whether 3 months of monotherapy with chloroquine influences the mRNA skin expression of interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) in nonirradiated and locally ultraviolet B (UVB) irradiated nondiseased skin of patients with systemic lupus erythematosus (SLE). PATIENTS/METHODS: Skin biopsies were collected from 14 patients with SLE 24 h after irradiation at one site and from an adjacent unirradiated site, before and after 3 months of chloroquine treatment. Messenger RNA levels for IL-1beta, IL-6 and TNF-alpha were determined by relative quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: There were no significant differences in the levels of mRNA cytokine expressions in the unirradiated sites before and after 3 months of chloroquine administration. In the irradiated sites, the expression of all three cytokine mRNA levels was significantly higher than in the unirradiated group, approximately 24 h after irradiation, before chloroquine treatment. Significantly lower expression of IL-1beta, IL-6 and TNF-alpha mRNAs was noted in irradiated skin samples after 3 months of chloroquine treatment. CONCLUSIONS: These results demonstrate the local inhibitory effects of chloroquine on UVB-induced upregulation in the mRNA expression of proinflammatory cytokines in irradiated skin of SLE patients, and provide further insight into the apparent immunomodulatory, anti-inflammatory and photoprotective properties of chloroquine.

Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex pathogenesis. Published data have revealed that serum levels of proinflammatory cytokines are increased in SLE patients. The aim of our study was to evaluate whether monotherapy with chloroquine phosphate affects IL-1beta, IL-6, IL-18 and TNF-alpha serum levels in SLE patients. The study group consisted of 25 SLE patients with mild or moderate disease activity and 25 age- and sex-matched healthy control subjects. In SLE patients the cytokine levels were measured just before and three months after starting chloroquine treatment at a dose of 125 mg twice daily. Although the majority of SLE patients had a low systemic lupus activity measure (SLAM) index, the levels of IL-6, IL-18 and TNF-alpha were significantly higher than in the control group. After three-months of chloroquine therapy the mean level of IL-6, IL-18 and TNF-alpha decreased significantly. Minimal erythema doses (MEDs) were significantly increased in SLE patients after three months of chloroquine therapy. The results indicate that chloroquine treatment lowers some proinflammatory cytokines and may provide a photoprotective effect.

Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus.

The 1982 ACR classification criteria have become de facto diagnostic criteria for systemic lupus erythematosus (SLE), but a review of the criteria is necessary to include recent diagnostic tests. The criteria were not developed with the help of dermatologists, and assign too much weight to the skin as one expression of a multiorgan disease. Consequently, patients with skin diseases are classified as SLE based mostly on skin symptoms. We discuss specific problems with each dermatologic criterion, but changes must await a new study. We suggest the following guidelines for such a study, aimed at revision of the criteria. 1) The SLE patient group should be recruited in part by dermatologists. 2) The study should evaluate an appropriate international ethnic/racial mix, including late onset SLE as well as pediatric patients. 3) All patients should have current laboratory and clinical evaluations, as suggested in the paper, to assure the criteria can be up-to-date. This includes anti-SS-A and anti-SS-B antibodies and skin biopsies for suspected cutaneous lupus erythematosus except for nonscarring alopecia and oral ulcers. 4) The study should be based on a series of transparent power calculations. 5) The control groups should represent relevant differential diagnoses in numbers large enough to assess diagnostic problems that might be specific to these differential diagnoses. In order to demonstrate specificity of the criteria with a 95% confidence interval between 90 and 100%, each control group of the above should have at least 73 patients.

Antimalarials in cutaneous lupus erythematosus: mechanisms of therapeutic benefit.

Antimalarials are arguably the best modality currently available for treating patients with cutaneous lupus erythematosus (LE). Although antimalarials have been used for decades in treating cutaneous LE, the precise mechanisms by which they provide therapeutic benefit are not well defined. The putative mechanisms by which antimalarials might provide therapeutic benefit to patients with cutaneous LE include a number of interrelated anti-inflammatory and immunosuppressive effects that include photoprotection, lysosomal stabilization, suppression of antigen presentation, and inhibition of prostaglandin and cytokine synthesis. If we had a more precise understanding of how antimalarials provide therapeutic benefit in cutaneous LE we might gain better insight into the pathogenic mechanisms of LE and ways of developing better therapies for afflicted patients.

Eccrine angiomatous hamartoma: a report of symmetric and painful lesions of the wrists.

Eccrine angiomatous hamartoma (EAH) is a rare, benign cutaneous lesion histologically defined as a proliferation of eccrine glands within a closely associated vascular stroma. Typically EAH presents as a solitary flesh-colored, hyperhidrotic, painful papule or plaque appearing at birth or during childhood. Only two previously reported cases have been described involving multiple, symmetrically located lesions. The occurrence of knuckle pads in patients with EAH has not been reported. We present an instance of multiple painful EAH lesions occurring symmetrically on the extensor wrists in a 14-year-old girl with knuckle pads.

Cutaneous lupus erythematosus.

Lupus erythematosus (LE) has many different clinical manifestations including a variety of cutaneous findings. Some of the cutaneous manifestations are not specific for LE, such as photosensitivity reactions, oral ulcers, alopecia, urticaria, vasculitis, vesiculo-bullous lesions, acral changes, cutaneous mucinoses, and cutaneous calcinosis. Other findings are specific for LE in that they are found only in patients who have lupus erythematosus. These LE-specific disorders include acute cutaneous LE, subacute cutaneous LE, and several forms of chronic cutaneous LE, including discoid LE. Skin biopsies are often helpful in differentiating LE-specific skin lesions from other disorders that can mimic them. Photoprotective measures and a number of drugs are useful in treating cutaneous LE.

Patients with cutaneous lupus erythematosus who smoke are less responsive to antimalarial treatment.

BACKGROUND: Reports suggest that cigarette smoking might interfere with the effectiveness of antimalarial therapy as first-line treatment for cutaneous lupus erythematosus. Patients refractory to this treatment often must be treated with potentially more toxic regimens. OBJECTIVE: Our purpose was to examine the effects of cigarette smoking on the therapeutic response to antimalarial agents in patients with discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). METHODS: A total of 61 patients (47 DLE, 14 SCLE) were selected on the basis of the following criteria: (1) skin biopsy was consistent with cutaneous LE, (2) a smoking history was available, and (3) an adequate trial of antimalarial therapy was completed. Patients were classified as antimalarial responders or nonresponders on the basis of descriptions in their medical records. Two-by-two table analysis was performed comparing response rates in smokers versus nonsmokers. RESULTS: A significant difference (P<.0002) in the antimalarial response rate was observed for smokers (40%) versus nonsmokers (90%). CONCLUSION: These results indicate that patients with cutaneous LE who smoke are significantly less likely to respond to antimalarial therapy.

Annular erythema of Sjögren's syndrome in a white woman.

Annular erythema of Sjögren's syndrome (AE-SS) is believed to be the Asian counterpart of subacute cutaneous lupus erythematosus (SCLE) in white persons. We report the second case of a white person with AE-SS, diagnosed by clinical and serologic findings, as well as the absence of histologic criteria for SCLE. The diagnosis of AE-SS was established by symptoms of xerophthalmia and xerostomia, as well as by examination of skin and salivary gland biopsy specimens. Evaluation showed the presence of anti-Ro(SS-A) and anti-La(SS-B) autoantibody, with the presence of anti-Ro(SS-A) antibody against the 60-kd, but not the 52-kd, epitope, a pattern frequently seen in both the Asians with AE-SS and in white patients with SCLE. Both skin and sicca symptoms were alleviated with combination antimalarial therapy, which included hydroxychloroquine and quinacrine. This case demonstrates that AE-SS can occur in white patients and that the autoantibody profile is similar to that described in Asians with this disease.

Gingival telangiectases: an underappreciated physical sign of juvenile dermatomyositis.

BACKGROUND: MEDLINE searches (1966-June 1969) failed to identify references that give detailed descriptions of the oral manifestations of dermatomyositis (DM). However, several reports predating MEDLINE provided more complete descriptions of oral lesions associated with DM. OBSERVATIONS: We describe 5 cases of juvenile DM with oral manifestations, primarily in the form of gingival telangiectases. These findings are compared with those descriptions found in earlier reports. CONCLUSIONS: Oral lesions in juvenile DM have rarely been reported. Mucous membrane involvement associated with DM may include telangiectases, edema, erosions, ulcers, and leukoplakia-like areas. In cases of DM, gingival telangiectases likely represent an underappreciated diagnostic finding analogous to nail-fold telangiectases.

Panniculitis in juvenile dermatomyositis.

Panniculitis is a rarely reported clinical finding in dermatomyositis. We present a 14-year-old African American boy with a 4-year history of dermatomyositis referred for evaluation of tender, indurated plaques and nodules on the trunk and proximal extremities. A biopsy specimen revealed epidermal and dermal changes consistent with dermatomyositis. Although calcification was absent, a striking lobular panniculitis was observed. A total of seven cases of clinical panniculitis in association with dermatomyositis have been published. As in our patient, it typically presents as indurated, tender plaques and nodules on the arms, thighs, and buttocks. Although in the vast majority of cases panniculitis found in association with dermatomyositis is subclinical and represents an incidental histopathologic finding, the case we present further emphasizes the need to recognize panniculitis as a rare, but clinically relevant pathologic feature seen in certain lesions of juvenile dermatomyositis.

Chilblain lupus erythematosus is associated with antibodies to SSA/Ro.

Chilblain lupus erythematosus (CL) of Hutchinson is a subtype of lupus erythematosus (LE) characterized by erythematous lesions induced by cold, damp climates. A number of patients affected by CL eventually develop features of systemic lupus erythematosus (SLE). We report here 9 patients with chilblain cutaneous lesions, 6 of them were affected by SLE and 2 by SCLE. The onset of CL preceded the diagnosis of LE, from 1 to 10 years in 3 cases, it was concurrent in one case and was subsequent in the remaining 4 cases. Raynaud's phenomenon and photosensitivity were other prominent clinical features in patients with CL. Nailfold capillaroscopy revealed pathological changes in every patient examined. ANA and anti-SSA/Ro antibodies were detected in all nine patients. Anti-SSB/La were detected in 2 cases, anti-Sm in one case, and anti-Sm and anti-RNP in a one case. Antibodies to dsDNA and complement consumption were found in the six patients with SLE. The fine specificity of anti-SSA/Ro was determined by immunoblotting: anti-60kD and anti-52 kD were detected in three sera, anti-60kD alone in 5 sera, while one serum did not blot. In conclusion, the present study suggests that chilblain LE is associated with SSA/Ro autoantibodies, as is SCLE, hypergammaglobulinemic purpura and neonatal lupus erythematosus.

Massive dystrophic calcinosis cutis secondary to chronic needle trauma.

Extensive dystrophic calcinosis cutis of the hips and anterolateral thighs in a woman with insulin-dependent diabetes mellitus is described. Clinical, histologic, and radiographic data are provided to familiarize the reader with this unique and newly described condition. We speculate that repetitive, chronic, needle trauma in susceptible persons can induce massive dystrophic calcinosis cutis.

Recombinant 52 kDa Ro(SSA) ELISA detects autoantibodies in Sjögren's syndrome sera that go undetected by conventional serologic assays.

OBJECTIVE: To determine the utility of a recombinant 52 kDa Ro(SSA) ELISA for detecting Ro autoantibodies in Sjögren's syndrome (SS) sera. METHODS: Several different groups of SS sera previously tested for Ro and La(SSB) autoantibodies in clinical diagnostic labs were tested by ELISA with a recombinant human 52 kDa Ro fusion protein. RESULTS: Five of 18 primary SS sera (28%) that had undetectable Ro and La autoantibodies by conventional immunodiffusion (ID) or ELISA in clinical diagnostic laboratories had significant reactivity with a recombinant 52 kDa Ro (r52) ELISA. On repeat testing these 5 sera were again negative for Ro and La antibodies by ELISA with purified 60 kDa Ro and La antigens, but 3 of these sera were reactive with r52 by immunoblot, and immunoprecipitated a 52 kDa protein from human cell extracts. Twelve of 12 primary SS sera that had detectable Ro autoantibodies by ID also reacted with the r52 ELISA, whereas none of 11 normal sera and only one of 27 ID-defined Ro negative systemic lupus erythematosus sera did. Eleven of 28 sera from patients with suspected SS were Ro positive by ID and 60 kDa Ro ELISA. All 11 were also Ro positive by the r52 ELISA. Two of the 28 suspected SS sera were Ro positive by the r52 Ro ELISA, but were Ro and La negative by ID and 60 kDa Ro and La ELISA. CONCLUSION: Anti-52 kDa Ro autoantibodies are frequently present in primary SS sera, but may go undetected by commonly used Ro serologic assays. Our r52 ELISA is more sensitive in detecting Ro antibodies in SS than conventional ID and 60 kDA Ro ELISA.

Disparate locations of the 52- and 60-kDa Ro/SS-A antigens in cultured human keratinocytes.

Anti-52- and anti-60-kDa Ro/SS-A (Ro) autoantibodies are produced by most patients with subacute cutaneous lupus erythematosus and neonatal lupus erythematosus and are thought to be pathogenic in these two disorders. To learn more about the epidermal antigens targeted by Ro autoantibodies, a panel of anti-52 and anti-60-kDa Ro antibodies was purified from human autoimmune sera and rabbit antisera and then used to: (i) determine the expression and location of the Ro antigens in human keratinocytes; (ii) clarify discrepancies in previous localization studies; and (iii) verify the existence of Ro autoantibodies that cross-react with the 52- and 60-kDa Ro antigens, as previously reported. By immunoblot analysis these antibodies demonstrate that 52- and 60-kDa Ro proteins are expressed in normal human skin and cultured keratinocytes. By indirect immunofluorescence studies with cultured human cells, the anti-52-kDa Ro antibodies produce fine granular cytoplasmic fluorescence and less intense nuclear fluorescence, with apparent nucleolar sparing. The anti-60-kDa Ro autoantibodies produce weak cytoplasmic fluorescence and intense coarse granular nuclear fluorescence with apparent nucleolar sparing. We found distinct differences in the intracellular localization of the 52- and 60-kDa Ro autoantigens. This difference suggests that the 52-and 60-kDa Ro antigens may have independent cellular functions. Finding 60-kDa Ro antigen predominantly in the nucleus challenges the notion that the majority of the intracellular 60-kDa Ro antigen is complexed with the cytoplasmic hY RNA. Additionally, our failure to find a cross-reactive epitope on these two proteins indicates that the 52-kDa Ro antigen is probably a true immunogen and not merely a protein that cross-reacts with anti-60-kDa Ro autoantibodies, as others have suggested.