玉腰暁子、他：全国疫学調査による難病受療患者数の推計―柳川斑5年間の成績．日本医事新報 3601:49-52,1993.
東條毅、他：膠原病4疾患における肺高血圧症の頻度に関する全国疫学調査．厚生省特定疾患混合性結合組織病調査研究班平成10年度報告書． p3-6, 1993.
D A Farrell, T A Medsger
Trigeminal neuropathy in progressive systemic sclerosis.
Am J Med. 1982 Jul;73(1):57-62.
Abstract/Text
Trigeminal neuropathy was identified in 16 (4 percent) of 442 consecutive patients with progressive systemic sclerosis (PSS) who were first evaluated during the period between 1972 and 1980. These cases, together with 25 others that are adequately documented in the literature, were reviewed and compared with the 426 cases of PSS (96 percent) without trigeminal neuropathy. Trigeminal neuropathy occurred most frequently in young women with PSS in overlap with other disorders, particularly the mixed connective tissue disease syndrome with clinical evidence of myositis. Serum antibodies to ribonucleoprotein were identified in nine (45 percent) of 20 PSS patients with trigeminal neuropathy as compared to 25 (8 percent) of 329 PSS patients without trigeminal neuropathy. Leukopenia, hypothyroidism, and Sjögren's syndrome were also found to be associated with trigeminal neuropathy.
Iana Souza Nascimento, Eloísa Bonfá, Jozélio Freire de Carvalho, Carla Gonçalves Saad, Margarete Borges Galhardo Vendramini, Manoel Jacobsen Teixeira, José Cláudio Marinho Nóbrega, Vilma Santos Trindade Viana
Clues for previously undiagnosed connective tissue disease in patients with trigeminal neuralgia.
J Clin Rheumatol. 2010 Aug;16(5):205-8. doi: 10.1097/RHU.0b013e3181e928e6.
Abstract/Text
BACKGROUND: Connective tissue diseases (CTD) may be associated with idiopathic trigeminal neuralgia (TN). The prevalence and diagnostic implications of this association are, however, not well established.
OBJECTIVES: The objective of this study was to evaluate, in TN patients, if rheumatologic clinical and laboratory findings could contribute to the early diagnosis of rheumatic diseases.
METHODS: Forty-six consecutive TN patients, 67% female, mean disease duration 8.78 +/- 7.25 years, and 47 controls were initially interviewed using a standard questionnaire based on common signs/symptoms of systemic lupus erythematosus, Sjögren syndrome, mixed CTD, and systemic sclerosis. Autoantibodies were detected by standard techniques. Those with rheumatologic complaints or positive autoantibodies were referred to the Rheumatology Outpatient Clinic for a more detailed evaluation. Secondary causes of TN were excluded.
RESULTS: The frequency of Raynaud phenomenon (P = 0.026) and ANA reactivity (P = 0.04) were significantly higher in TN patients compared with controls. Fourteen TN patients were ANA positive. Seven of them reported concomitant rheumatic complaints, and interestingly, diffuse CTD was diagnosed in 4 (57%) of these patients: 1 systemic lupus erythematosus; 2 Sjögren syndrome; and 1 undifferentiated disease with scleritis and positive parotid scintigraphy. In all cases, TN preceded by at least 10 months the rheumatologic signs/symptoms. Moreover, these 4 TN patients with CTD had a higher frequency of sicca symptoms (P = 0.001) and higher titers of ANA (>or=1:320) (P = 0.006) than the remaining 42 TN patients without CTD diagnoses. Sixteen patients had isolated laboratory or clinical abnormalities, and none of them had CTD diagnoses.
CONCLUSIONS: The concomitant presence of sicca symptoms and high titer ANA are clues for the early investigation of rheumatic diseases in TN patients.
Virginia Steen, Thomas A Medsger
Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement.
Arthritis Rheum. 2003 Feb;48(2):516-22. doi: 10.1002/art.10775.
Abstract/Text
OBJECTIVE: To determine whether there are factors, such as the diffusing capacity for carbon monoxide (DLCO) or pulmonary artery pressure (PAP) on echocardiogram, that can predict the development of pulmonary hypertension (PHT) in patients with limited scleroderma.
METHODS: Using the large Pittsburgh Scleroderma Databank, 106 patients who had the diagnosis of PHT after January 1, 1982, were matched with 106 controls by scleroderma subtype, age, sex, race, disease duration, and the mean time to the diagnosis of PHT after the initial Pittsburgh visit. Autoantibodies, vascular features, use of calcium channel blockers, extent of pulmonary function, and echocardiogram findings were determined at any time prior to the diagnosis of PHT (or prior to the matched time in controls).
RESULTS: Patients with PHT had a mean DLCO of 52% of predicted at an average of 4.5 years prior to the diagnosis of PHT. This was markedly decreased compared with the values in controls, whose mean DLCO was 81% of predicted (P < 0.0001). The estimated mean PAP on echocardiogram was only slightly higher in the PHT patients compared with controls (34 mm Hg versus 29 mm Hg; P not significant). Nineteen PHT patients had 4 serial measurements of the DLCO during the 15 years prior to the diagnosis of PHT. The initial mean DLCO was 80% of predicted, which decreased in a linear manner to a mean of 35% of predicted at the time of diagnosis of PHT, whereas the value in controls remained at approximately 80% of predicted (P < 0.0001). PHT patients had more severe Raynaud's phenomenon and more severe digital tip ulcers, but they used calcium channel blockers significantly less frequently (37% versus 61% of controls; P < 0.01). The predominance of nucleolar autoantibodies and the absence of anti-Scl 70 antibody were associated with PHT.
CONCLUSION: A decreasing DLCO is an excellent predictor of the subsequent development of isolated PHT in limited scleroderma. The DLCO may be significantly decreased for many years prior to the diagnosis of PHT. The presence of autoantibodies and the PAP may also be helpful predictors. The long-term use of calcium channel blockers may be protective, but newer agents that are more effective in treating PHT may also be helpful in altering the natural history of this serious complication in limited scleroderma.
Y Allanore, D Borderie, J Avouac, D Zerkak, C Meune, E Hachulla, L Mouthon, L Guillevin, O Meyer, O G Ekindjian, S Weber, A Kahan
High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis.
Arthritis Rheum. 2008 Jan;58(1):284-91. doi: 10.1002/art.23187.
Abstract/Text
OBJECTIVE: To evaluate predictors of pulmonary arterial hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc).
METHODS: Routine clinical assessments as well as measurements of the diffusing capacity for carbon monoxide/alveolar volume (DLCO/VA) ratio and N-terminal pro-brain natriuretic peptide (NT-proBNP) level were performed in a prospective cohort of 101 SSc patients who did not have PAH or severe comorbidities. After a planned 36-month followup, we evaluated the predictive value of these parameters for the development of precapillary PAH, as demonstrated by cardiac catheterization, disease progression, and death. Criteria for cardiac catheterization were a systolic pulmonary artery pressure (PAP) of >40 mm Hg on echocardiography, a DLCO value of <50% without pulmonary fibrosis, and unexplained dyspnea.
RESULTS: Eight patients developed PAH, 29 had disease progression, and 10 died during a median followup of 29 months. Kaplan-Meier analysis identified the following baseline parameters as being predictors of PAH: DLCO/VA ratio <70% or <60% (P<0.01 for each comparison), elevated plasma NT-proBNP level (>97th percentile of normal; P = 0.005), echocardiographically estimated systolic PAP >40 mm Hg (P=0.08), and erythrocyte sedimentation rate >28 mm/hour (P=0.015). In multivariate analyses, an elevated baseline NT-proBNP level (hazard ratio [HR] 9.97 [95% confidence interval (95% CI) 1.69-62.42]) and a DLCO/VA ratio <60% (HR 36.66 [95% CI 3.45-387.6]) were predictors of the occurrence of PAH during followup. An increased NT-proBNP level together with a decreased DLCO/VA ratio of <70% was highly predictive of the occurrence of PAH during followup (HR 47.20 [95% CI 4.90-450.33]).
CONCLUSION: This prospective study identified a decreased DLCO/VA ratio and an increased NT-proBNP as predictors of PAH in SSc. Use of these markers should result in improved PAH risk stratification and allow earlier initiation of therapy.
Yoshiya Tanaka, Masataka Kuwana, Takao Fujii, Hideto Kameda, Yoshinao Muro, Keishi Fujio, Yasuhiko Itoh, Hidekata Yasuoka, Shusaku Fukaya, Konomi Ashihara, Daisuke Hirano, Koichiro Ohmura, Yuya Tabuchi, Hisanori Hasegawa, Ryo Matsumiya, Yuichiro Shirai, Takehisa Ogura, Yumi Tsuchida, Mariko Ogawa-Momohara, Hidehiko Narazaki, Yoshino Inoue, Ippei Miyagawa, Kazuhisa Nakano, Shintaro Hirata, Masaaki Mori
2019 Diagnostic criteria for mixed connective tissue disease (MCTD): From the Japan research committee of the ministry of health, labor, and welfare for systemic autoimmune diseases.
Mod Rheumatol. 2021 Jan;31(1):29-33. doi: 10.1080/14397595.2019.1709944. Epub 2020 Jan 7.
Abstract/Text
OBJECTIVE: To update and revise the diagnostic criteria for mixed connective tissue disease (MCTD) issued by the Japan Research Committee of the Ministry of Health, Labor, and Welfare (MHLW), a round table discussion by experts from rheumatology, dermatology, and pediatric medicine was conducted in multiple occasions.
METHODS: The definition of MCTD, and items included in the diagnostic criteria were generated by consensus method and evaluation using clinical data of typical and borderline cases of MCTD, by applying to the diagnostic criteria for MCTD proposed in 1996 and 2004 by the Research Committee of MHLW.
RESULTS: To the end, all committee members reached consensus. Then, the criteria were assessed in an independent validation cohort and tested against preexisting criteria. The revised criteria facilitate an understanding of the overall picture of this disease by describing the concept of MCTD, common manifestations, immunological manifestation and characteristic organ involvement. Conditions with characteristic organ involvement include pulmonary arterial hypertension, aseptic meningitis and trigeminal neuropathy. Even if the overlapping manifestations are absent, MCTD can be diagnosed based on the presence of the characteristic organ involvement. Furthermore, the criteria were validated for applicability in actual clinical cases, and public comments were solicited from the Japan College of Rheumatology and other associated societies.
CONCLUSION: After being reviewed through public comments, the revised diagnostic criteria have been finalized.
Kelley’s Textbook of Rheumatology, 9th edition. p1447.
三森経世 ほか：混合性結合組織病診療ガイドライン(改訂第3版)、p51-3.
R F Bernstein
Ibuprofen-related meningitis in mixed connective tissue disease.
Ann Intern Med. 1980 Feb;92(2 Pt 1):206-7.
Abstract/Text
R M Bennett, D J O'Connell
Mixed connective tisssue disease: a clinicopathologic study of 20 cases.
Semin Arthritis Rheum. 1980 Aug;10(1):25-51.
Abstract/Text
Olivier Sanchez, Olivier Sitbon, Xavier Jaïs, Gérald Simonneau, Marc Humbert
Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension.
Chest. 2006 Jul;130(1):182-9. doi: 10.1378/chest.130.1.182.
Abstract/Text
STUDY OBJECTIVE: Immune and inflammatory mechanisms could play a significant role in pulmonary arterial hypertension (PAH) genesis or progression, especially in patients with connective tissue diseases. Immunosuppressive therapy should be better evaluated in this setting.Study design: Monocentric retrospective study.
PATIENTS: We reviewed the clinical and hemodynamic effects of immunosuppressants administered as first-line monotherapy to 28 consecutive patients with connective tissue disease-associated PAH.
INTERVENTIONS: All patients received a monthly IV bolus of cyclophosphamide, 600 mg/m2, for at least 3 months, and 22 of 28 patients received systemic glucocorticosteroids. Responders to immunosuppressive therapy were defined as patients who remained in New York Heart Association (NYHA) functional class I or II with sustained hemodynamic improvement after at least 1 year of immunosuppressive therapy without addition of prostanoids, phosphodiesterase type 5 inhibitors, or endothelin receptor antagonists.
RESULTS: Eight of 28 patients (systemic lupus erythematosus [SLE], n = 5; mixed connective tissue disease [MCTD], n = 3) [29%] were responders. These patients had a significantly improved 6-min walking distance (available in five patients) and a significant improvement in hemodynamic function. No patients with systemic sclerosis responded, while 5 of 12 patients with SLE and 3 of 8 patients with MCTD did respond. Survival analysis indicated that responders had a better survival than nonresponders. Patients with a lower baseline NYHA functional class and better baseline pulmonary hemodynamics (p < 0.05) were more likely to benefit from immunosuppressive therapy.
CONCLUSION: PAH associated with SLE or MCTD might respond to a treatment combining glucocorticosteroids and cyclophosphamide.
混合性結合組織病の診療ガイドライン(改訂第3版).
循環器病学の診断と治療に関するガイドライン(2005年度合同研究班報告)：肺高血圧治療ガイドライン(2006年改訂版).
M Hoffman, R G Gray
Ibuprofen-induced meningitis in mixed connective tissue disease.
Clin Rheumatol. 1982 Jun;1(2):128-30.
Abstract/Text
A young Black woman with mixed connective tissue disease (MCTD) developed an aseptic meningitis after receiving ibuprofen. The meningeal reaction, reported infrequently in systemic lupus erythematosus (SLE) and only once previously in MCTD, was characterized by a predominantly polymorphonuclear cerebrospinal fluid (CSF) pleocytosis and depression of CSF glucose. Reversible renal insufficiency also occurred. Features suggestive of a hypersensitivity reaction included pruritus, conjunctivitis, facial oedema, desquamation of the palms and soles, and subsequent near total alopecia. Meningeal signs responded rapidly to systemic corticosteroid therapy. Patients with MCTD as well as those with SLE may be at peculiar risk of developing this uncommon reaction to ibuprofen.
J Okada, T Hamana, H Kondo
Anti-U1RNP antibody and aseptic meningitis in connective tissue diseases.
Scand J Rheumatol. 2003;32(4):247-52.
Abstract/Text
OBJECTIVE: To investigate the relationship between aseptic meningitis and anti-U1RNP antibody in patients diagnosed with CTD.
METHODS: Fourteen patients with aseptic meningitis were selected from among patients with CTDs who had visited our hospital. We analyzed their medical records to clarify the clinical and immunological features of aseptic meningitis.
RESULTS: A total of 14 patients with aseptic meningitis were subsequently diagnosed as having either SLE (seven cases), MCTD (four), UCTD (one), overlap syndrome (one), or Sjögren's syndrome (one). Eight of the 14 patients had received NSAIDs, such as sulindac, naproxen, or loxoprofen, before the onset of aseptic meningitis. CRP levels were increased (mean +/- SD: 7.1 +/- 7.1 mg/dL) and CRP levels (10.4 +/- 7.7) in the drug-induced group were significantly increased (p < 0.01). The anti-U1RNP antibody was found in 13 of the 14 patients. There were no significant differences in cerebrospinal fluid findings between the drug-induced group and the non-drug-induced group.
CONCLUSIONS: SLE or MCTD patients with aseptic meningitis tend to have anti-U1RNP antibody.
Y Mizushima, Y Shiokawa, M Homma, S Kashiwazaki, Y Ichikawa, H Hashimoto, A Sakuma
A multicenter double blind controlled study of lipo-PGE1, PGE1 incorporated in lipid microspheres, in peripheral vascular disease secondary to connective tissue disorders.
J Rheumatol. 1987 Feb;14(1):97-101.
Abstract/Text
Lipo-PGE1 is a drug preparation of PGE1 (prostaglandin E1) incorporated in lipid microspheres similar in properties to liposomes. A multicenter, placebo controlled, double blind test of lipo-PGE1 was carried out in patients with severe peripheral vascular disease secondary to diffuse connective tissue disorders. A total of 135 patients received a 90 min intravenous infusion of either 10 micrograms lipo-PGE1 or placebo every day for 4 weeks. A significant improvement was noted in the lipo-PGE1 group compared with the placebo group in the final overall improvement of peripheral vascular disease (p less than 0.001) and in the healing of ulcers (p less than 0.01), whereas, there was no difference in Raynaud's syndrome between the 2 groups. Side effects in the lipo-PGE1 group were few and were no different from controls. These results indicate that lipo-PGE1 at a low dose is beneficial in the treatment of peripheral vascular disease, and that lipid microspheres are useful as a drug delivery system for such purposes.
Theresa Tingey, Jenny Shu, Joseph Smuczek, Janet Pope
Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis.
Arthritis Care Res (Hoboken). 2013 Sep;65(9):1460-71. doi: 10.1002/acr.22018.
Abstract/Text
OBJECTIVE: To assess the efficacy of therapies in healing and preventing digital ulcers (DUs) in systemic sclerosis (SSc; scleroderma).
METHODS: Medline and EMBASE databases, and American College of Rheumatology and European League Against Rheumatism abstracts, were searched. Randomized controlled trials (RCTs) with outcomes investigating healing or prevention of DUs in SSc and comparing a pharmacologic therapy with placebo or an active agent were included. The pooled risk ratios (RRs) using the fixed-effects model were calculated and heterogeneity was tested using the I(2) statistic.
RESULTS: Sixty studies were found; 19 were not randomized, and 10 did not give DU quantitative data or no comparison of a different drug, leaving 31 RCTs with a total of 1,989 patients. Quality was 3 of 5 or less for 11 trials. DUs were not the primary outcome in many RCTs. Phosphodiesterase type 5 (PDE-5) inhibitors were significant for DU healing (RR 3.28 [95% confidence interval (95% CI) 1.32, 8.13], P = 0.01). Two large bosentan trials were significant for mean number of new DUs (standardized mean difference [SMD] -0.34 [95% CI -0.57, -0.11], P = 0.004). Oral prostacyclins were not statistically different from placebo, but intravenous (IV) iloprost prevented new DUs (SMD 0.77 [95% CI -1.46, -0.08], P = 0.03). Single trials for atorvastatin and vitamin E were positive in the prevention and healing of DU, respectively. There were many negative trials: antiplatelet therapy, oral N-acetylcysteine, heparin, dimethyl sulfoxide, ketanserin, prazosin, prostaglandin E1, cyclofenil, quinapril, and topical nitroglycerin formulation.
CONCLUSION: Small sample sizes, few comparative trials, and heterogeneity limits the conclusions. The results suggest a role for PDE-5 inhibitors in the healing of DUs; bosentan and IV iloprost may prevent new DUs.
Copyright © 2013 by the American College of Rheumatology.
