Mixed connective tissue disease

Mixed connective tissue disease (MCTD) was first described by Gordon Sharp,¹ in 1972, as a distinct connective tissue disorder characterized by overlapping features of systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS), and dermato/polymyositis (DP/PM). This can be distinguished from other overlap syndromes of the connective tissue diseases by the presence of high titers of an antinuclear antibody with specificity for ribonuclear protein (RNP).^1,2 Initial reports described the following additional characteristics of MCTD patients: a good therapeutic response to systemic corticosteroid therapy, a very low incidence of significant renal involvement, and a better prognosis than for SLE or PSS.^1–4 Currentopinion is divided, but in general MCTD is considered to be an overlapping clinical expression in the evolution of a more classic connective tissue disease, usually PSS. The prognosis is less favorable than once thought, particularly when the MCTD is dominated by features of PSS.^5–8     

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.     

间接血凝法在测定SLE患者血清中抗ds-DNA抗体的意义

抗核抗体(ANA)的测定已较普遍地应,用于临床诊断,由于它的非特异性对诊断系统型红斑性狼疮(SLE)仍有一定的局限性.抗双链去氧核糖核酸(ds-DNA,以下简称DNA)抗体的测定对诊断SLE有较大的特异性^(1,2),目前已用作ANA侧定后进二步明确诊断、了解病情特别是反映狼疮性肾炎的有用实验室指标之^③.测定坑DNA抗体的方法很多,考虑到方法的简便,易于推广,我们采用了间接血凝法.     

Subcutaneous calcification of the lower legs in a patient with mixed connective tissue disease

A 56-year-old woman who had been treated for mixed connective tissue disease (MCTD) noticed a skin ulcer on the lower leg. There was no history of trauma. X-rays of the lower legs showed extensive calcification in the soft tissue. Biopsied tissue from the ulcer showed marked calcium deposition with necrosis. Laboratory findings revealed normal serum calcium and phosphate levels and normal parathyroid function. On the basis of these findings, we diagnosed skin ulcer due to subcutaneous dystrophic calcification associated with MCTD. The ulcer was gradually reduced in size and epithelialized by treatment with local debridement and antibiotics.     

High serum levels of antibodies against the recombinant 70 kDa ribonucleoprotein are useful for diagnosing mixed connective tissue disease

BACKGROUND: Anti-Sm antibodies and anti-RNP antibodies are considered to be diagnostic markers of systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). However, cross-reactivity between the antibodies diminishes their discriminating specificity between these diagnoses. OBJECTIVE: We examined whether we could achieve better differentiation between these two disease entities using recombinant antigens to RNP70 and SmD and quantitative immunoassays. PATIENTS/METHODS: Sera from 51 patients with SLE and 10 patients with MCTD and from a control group of 59 patients were used in a cross-sectional setting. Semiquantitative ELISAs for the detection of antibodies to RNP-70, RNP-A, RNP-C, SmBB' and SmD were used and the results were compared to conventional ELISA tests using U(1)-snRNP and a mixture of SmBB' and SmD as antigenic substrates. RESULTS: Sera from MCTD patients showed higher levels of anti-RNP-70 antibodies than sera from SLE patients. Levels of anti-SmBB' or anti-SmD antibodies were not significantly different between SLE and MCTD sera. However, the presence of antibodies directed against SmD was more frequent in SLE. CONCLUSIONS: Our results suggest that the use of RNP-70 and SmD antigens may increase the practical value of immunoassays used to confirm a diagnosis of SLE or MCTD in patients with connective tissue disease.     

An adult case of mixed connective tissue disease associated with myocardial infarction

A 36-year-old Japanese woman with mixed connective tissue disease (MCTD) was treated with systemic Vitamin E and developed sudden myocardial infarction. The diagnosis of MCTD was based on clinical and serological findings. Since she developed pericarditis with high fever on the occasion of the attack of myocardial infarction, she was treated with systemic corticosteroid and recovered well. Although MCTD had been recognized as a disease with good response to corticosteroid and good prognosis, some cases suffer from interstitial pneumonia, pulmonary hypertension and myocardial infarction with poor prognosis.     

Mixed connective tissue disease.

Three patients with mixed connective tissue disease (MCTD) had clinical features that included a high incidence of Raynaud phenomenon, arthritis, myositis, and swollen hands. The diagnostic laboratory test result was the presence of high titers of antibody to extractable nuclear antigen. These antibody titers are notably reduced or abolished in patients with MCTD when the tanned red blood cells that are used in the test are pretreated with ribonuclease. Speckled antinuclear antibodies were present in all patients. Patients with MCTD have a low incidence of renal disease, are responsive to treatment with prednisone, and have a good prognosis.     

抗RNP抗体与结缔组织病

本文报告以小牛胸腺提取物(ENA),并用被动血凝法和对流免疫电泳法,测定5家医院785例患者,分析150例抗体阳性患者的结果.抗RNP抗体在混合性结缔组织病(MCTD)中阳性率最高,为100%.该抗体也见于其他结缔组织病(CTD),偶见于非CTD,但血清效价低.高效价的抗RNP抗体有助丁MCTD的诊断,可作为该病的血清学标记.抗RNP抗体同某些临床表现相伴,可能同其发病机理有关.通过本研究,我们认为MCTD为一个独立疾病,其具有一组特征性临床表现和免疫学异常. Sharp(1983)提出的MCTD诊断标准具有一定的实用意义,值得进一步探讨.     

混合性结缔组织病皮肤表皮细胞核染色的价值

采用 IIF法对 2 32例 CTD患者的外观正常皮肤进行了免疫荧光研究。结果发现 10 0 %的MCTD患者的表皮细胞核有 S型 Ig G沉积 ,并显著高于 SL E患者 ( 6.6% ) ,同时血清伴有高滴度、单一的抗 RNP抗体和高滴度的 S型 ANA。因此 ,S型 Ig G ENS和高滴度单一抗 RNP抗体之间具有高度的相关性。我们认为 S型 Ig G ENS可作为 MCTD的免疫病理学特征 ,其对 MCTD具有重要的辅助诊断价值     

Immunofluorescence studies in progressive systemic sclerosis (scleroderma) and mixed connective tissue disease

Immunofluorescence (IF) investigations of the skin were performed in thirty patients with progressive systemic sclerosis (scleroderma) and eight patients with mixed connective tissue disease (MCTD). The results show that speckled epidermal nuclear immunoglobulin deposition occurs not only in MCTD but also in true scleroderma. Granular IgM deposition at the dermo-epidermal junction of light-exposed skin was detected in both groups of patients, but six of eight MCTD patients also showed a granular IgM band in non-exposed skin. Antinuclear antibodies (ANA) were demonstrated in the sera of 96% and 100% of patients with scleroderma and MCTD respectively. The pattern of nuclear IF staining in scleroderma included dense fine speckles, large coarse speckles, threads, nucleolar and centromere staining. In MCTD, by contrast, the ANA staining pattern consisted of threads. The significance of ANA titres and immunological specificities for the in vivo reaction of serum ANA with epidermal nuclear antigens is discussed.     

Pseudoporphyria associated with Relafen therapy

Various oral medications including nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with pseudoporphyria, although the pathogenetic basis has not been elucidated. A novel NSAID nabumetone (Relafen) has become popular because of its minimal gastrointestinal side effects. Its association with pseudoporphyria is not reported save for its listing in the Physician's Desk Reference (PDR) as a possible side effect. Biopsies of lesional skin from 4 patients manifesting blisters and erosions on the hands and face within 4 months of starting nabumetone were submitted for light microscopic and immunofluorescent (IF) studies. Histories and serology were obtained. Two patients had rheumatoid arthritis (RA), 1 had mixed connective tissue disease (MCTD), and 1 received diltiazem. All 4 had antinuclear antibodies. Characteristic clinical, light microscopic and IF features in the absence of elevated urine porphyrin levels confirmed a diagnosis of pseudoporphyria in all 4 patients. Biopsies in three patients showed features attributed to underlying connective tissue disease (CTD), including ectasia of the superficial vascular plexus, mild leukocytoclastic vasculitis, superficial and deep perivascular lymphocytic infiltrates with dermal mucinosis, granular deposition of IgM along the dermoepidermal junction indicative of a positive lupus band test, and of IgG and C5b-9 within keratinocytes. Nabumetone (Relafen) can provoke pseudoporphyria; an underlying CTD diathesis may be a predisposing factor.     

MCTD – Mixed Connective Tissue Disease

Mixed connective tissue disease is a disease entity characterized by overlapping symptoms of lupus erythematosus (LE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA). Diagnostic criteria include high titers of antibodies against U1RNP as well as the presence of at least 3 of 5 of the following clinical features: edema of hands, synovitis, myositis, Raynaud phenomenon and acrosclerosis. In terms of the pathogenesis, genetic as well as infectious (viral) factors appear to play a role. The acceptance of MCTD as a distinct disease entity is controversial. Terms such as ”undifferentiated connective tissue disease“ or ”overlapping syndromes“ are not helpful. One‐quarter of MCTD patients transform into LE, while one‐third progress to SSc. Therapeutic recommendations are glucocorticoids in combination with immunosuppressive agents and endothelin receptor antagonists. Double blind studies are not available. The prognosis is relatively good. Causes of death include pulmonary hypertension, infections and both pulmonary and cardiac failure.     

Kollagenosen im Kindesalter

Connective tissue diseases are a heterogeneous group of chronic multisystem inflammatory disorders including systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS), dermato- (DM) and polymyositis (PM), mixed connective tissue disease (MCTD), and Sjögren’s syndrome (SS). Patients can present with similar clinical features, particularly during the first onset of symptoms, which frequently makes the diagnosis of a specific disease difficult. The incidence of connective tissue diseases is much lower in children than adults; however, the clinical picture is more variable. Clinical signs, such as fatigue, fever, or weight loss, may precede any systemic organ involvement and in children, mucocutaneous manifestations develop most frequently during the varying disease course. This review summarizes recent information on epidemiology, clinical manifestations, diagnostic procedures, and treatment strategies of the different connective tissue diseases, concentrating on specific problems in childhood.     

Wound,pressure ulcer and burn guidelines – 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.     

The wound/burn guidelines – 4: Guidelines for the management of skin ulcers associated with connective tissue disease/vasculitis

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.     

Coexistence of mucous membrane pemphigoid and connective‐tissue disease

Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease that predominantly affects the mucosa. We report eight patients with MMP who also had systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), or both. Eight women (six white, two Hispanic; mean age of onset 53.5 years [range 44–68]) were studied. In four patients, both diseases were detected simultaneously, and in the other four patients, MMP preceded SLE or MCTD. MMP was widespread and resistant to conventional immunosuppressive therapy, but responded to intravenous immunoglobulin (IVIg). During a mean follow‐up of 10.25 years (range 6–18), three patients had stable SLE/MCTD, whereas in the other five patients the SLE/MCTD required systemic corticosteroids either with or without immunosuppressive agents. Renal, serosal, pulmonary and neurological features were not observed in any patient. At the time of reporting, the MMP was in a prolonged sustained remission in all eight patients. The SLE/MCTD remained mild, did not involve vital organs and had continued with low‐grade activity. In summary, we report the simultaneous occurrence of two rare diseases in a group of patients.     

A CASE OF SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS WITH A HIGH TITER OF RNP ANTIBODY

A 30-year-old man developed severe erosive lesions in his oral cavity and transient Raynaud's phenomenon followed by discoid lupus erythematosus (DLE)-like lesions and non-scarring erythema. He had a high titer of RNP antibody as well. Widespread DLE (w-DLE), subacute cutaneous lupus erythematosus (SCLE) and mixed connective tissue disease (MCTD) were suspected as his condition. Finally we diagnosed him as having SCLE accompanied with a high titer of RNP antibody.     

Cutaneous vasculitis update: neutrophilic muscular vessel and eosinophilic, granulomatous, and lymphocytic vasculitis syndromes

Most biopsies of cutaneous vasculitis will exhibit a small vessel neutrophilic vasculitis [leukocytoclastic vasculitis (LCV)] that is associated with immune complexes on direct immunofluorescence examination or, less commonly, antineutrophilic cytoplasmic antibodies (ANCA) by indirect immunofluorescence testing. Is in uncommon for skin biopsy to reveal solely a neutrophilic arteritis signifying the presence of cutaneous polyarteritis nodosa or, if accompanied by significant lobular panniculitis, nodular vasculitis/erythema induratum. In other cases, cutaneous vascular damage (fibrinoid necrosis, muscular vessel wall disruption, or endarteritis obliterans) will be mediated by a nonneutrophilic inflammatory infiltrate. Eosinophilic vasculitis can be a primary (idiopathic) process that overlaps with hypereosinophilic syndrome, or it can be a secondary vasculitis associated with connective tissue disease or parasite infestation. Authentic cutaneous granulomatous vasculitis (versus vasculitis with extravascular granulomas) can represent a cutaneous manifestation of giant cell arteritis, an eruption secondary to systemic disease such as Crohn's disease or sarcoidosis, or a localized disorder, often a post-herpes zoster (HZ) phenomenon. Lymphocytic vasculitis is a histologic reaction pattern that correlates with broad clinical differential diagnosis, which includes connective tissue disease - mostly systemic lupus erythematosus (SLE), endothelial infection by Rickettsia and viruses, idiopathic lichenoid dermatoses such as perniosis or ulcerative necrotic Mucha-Habermann disease, and angiocentric cutaneous T-cell lymphomas. Skin biopsy extending into the subcutis, identifying the dominant inflammatory cell and caliber of vessels affected, extravascular histologic clues such as presence of lichenoid dermatitis or panniculitis, and correlation with clinical data allows for accurate diagnosis of these uncommon vasculitic entities.     

Cutaneous Manifestations of Mixed Connective Tissue Disease: Study from a Tertiary Care Hospital in Eastern India

Context:

Mixed connective tissue disorder is an uncommon disease. Some scientists are reluctant to recognize it as a separate entity. Some others have defined this ailment. Cutaneous features of this condition are unique. Researchers from India have described these features to relate to those described in the studies from other parts of the globe.

Aims:

This study aims to delineate the skin manifestations of clearly defined mixed connective tissue disease (MCTD) patients, to compare them with those established as overlap syndrome, and to relate them with studies from other parts of the globe.

Settings and Design:

Successive patients who fulfilled the specific criteria for MCTD presenting in the skin outpatient department of a tertiary care hospital in eastern India were clinically examined from 2009 for 3 years.

Materials and Methods:

The number of participants was 23 and the dermatological features of these were compared with 22 patients with overlap syndrome. The antibody to uridine-rich U1 ribonucleoprotein was measured for all patients.

Statistical Analysis Used:

SPSS (Version 17) and MedCalc (Version 11.6).

Results:

The Male: Female ratio among the MCTD patients was 1:6.67 and that of the overlap syndrome was 1:10. Twenty patients of the MCTD group presented with synovitis as against only seven in the overlap group. Raynaud''s phenomenon was present in some of the subjects. Puffy fingers were rare in our study. Facial numbness was reported by four of those suffering from MCTD. Antinuclear antibody (ANA) was essentially of a speckled pattern in this disease

Conclusions:

Cutaneous indicators of MCTD are distinct from overlap syndrome. Knowledge of these manifestations prevalent in a region may lead to early diagnosis of the disease.     

The evolution of lesions in erythema elevatum diutinum

We obtained biopsies from early, fully developed, and late lesions of erythema elevatum diutinum (EED) in a 49-year-old man. The histologic and electron-microscopic findings were compared with those reported in the literature and three other cases from our files. Early lesions show leukocytoclastic vasculitis with capillary proliferation. Later lesions show vasculitis, dermal aggregates of neutrophils, fibrosis, and areas of granulation tissue. Newly formed vessels in granulation tissue may be more susceptible to damage by immune complexes, and the early formation of granulation tissue in EED may prevent an early resolution of vasculitis. Damage to dermal connective tissue in EED incites either scarring or, rarely, a fibrohistiocytic proliferation. Ultrastructural examination of one case showed histiocytes with myelin figures and intracellular lipid and cholesterol.