Musculoskeletal manifestations occur predominantly in patients with later-onset familial Mediterranean fever: Data from a multicenter, prospective national cohort study in Japan.

BACKGROUND: We showed previously that Japanese individuals with familial Mediterranean fever (FMF) have a more atypical phenotype compared to endemic areas. The clinical differences between young-onset FMF (YOFMF), adult-onset FMF (AOFMF), and late-onset FMF (LOFMF) in Japan are unclear. METHODS: We enrolled 395 consecutive patients. We defined YOFMF, AOFMF, and LOFMF as the onset of FMF at < 20, 20-39, and ≥ 40 years of age, respectively. We compared clinical manifestations and MEFV mutations patterns among these groups. RESULTS: Median ages at onset were YOFMF 12.5 years (n = 182), AOFMF 28 years (n = 115), and LOFMF 51 years (n = 90). A family history, MEFV mutations in exon 10, and more than two MEFV mutations were significantly more frequent in the earlier-onset groups (p < 0.01, p < 0.0001, and p < 0.001, respectively). In the accompanying manifestations, thoracic and abdominal pain were significantly more frequent in the earlier-onset groups (p < 0.01 and p < 0.0001, respectively), whereas arthritis and myalgia were significantly more frequent in the later-onset groups (p < 0.0001 and p < 0.01, respectively). The multiple logistic regression analysis revealed that the presence of MEFV exon 10 mutations and earlier onset were significantly associated with serositis, whereas the absence of MEFV exon 10 mutations, later onset, and the presence of erysipelas-like erythema were significantly associated with musculoskeletal manifestations. There was no significant between-group difference in the responsiveness to colchicine. CONCLUSIONS: Our results indicate that the later-onset FMF patients had a lower percentage of MEFV mutations in exon 10 and predominantly presented arthritis and myalgia. It is important to distinguish their FMF from other inflammatory diseases.

Subclinical inflammation in a case of menstruation-induced familial Mediterranean fever: A case report.

RATIONALE: Because most patients with familial Mediterranean fever (FMF) have attacks without any prodromal symptoms, and since it is suggested that patients with FMF have subclinical inflammation even during remission, a daily continuous administration of colchicine is recommended for patients with FMF even during remission. However, it is possible that intermittent colchicine therapy only during FMF attacks prevents the attacks completely in patients with FMF with expectable attacks. PATIENT CONCERNS: A 31-year-old Japanese woman suffered high fever and arthralgia lasting for 2 to 3 days after each menstrual period's start. She was admitted to our hospital, and colchicine was administered immediately after her next period's start, and the febrile attack was completely prevented. DIAGNOSES: We eventually diagnosed typical FMF. INTERVENTIONS: Her remission has been maintained by intermittent colchicine therapy. OUTCOMES: The genetic analysis revealed the G304R heterozygous mutation in exon 2 of the MEFV gene. Cytokine analysis suggested subclinical inflammation during the remission period. LESSONS: This case suggests that taking an extensive medical history (including the relationship between fever attack and menstruation) is important in the diagnosis of female patients with FMF. This case also suggests that a continuous administration of colchicine may have to be considered to regulate subclinical inflammation even in patients with FMF with completely expectable attacks.

Anti-MDA5 Antibody-positive Dermatomyositis Complicated by Autoimmune-associated Hemophagocytic Syndrome That Was Successfully Treated with Immunosuppressive Therapy and Plasmapheresis.

A 56-year-old Japanese woman with muscle weakness, increased creatine kinase and aldolase levels, and characteristic cutaneous lesions was diagnosed with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 antibody)-positive dermatomyositis. She also had interstitial lung disease (ILD). After corticosteroid and tacrolimus combination therapy was started, bicytopenia and elevated serum ferritin and transaminase emerged. Because the bone marrow tissues were hypoplastic with hemophagocytes, she was diagnosed with concomitant autoimmune-associated hemophagocytic syndrome (HPS). Intravenous cyclophosphamide pulse therapy and plasmapheresis were performed. The laboratory findings indicated improved abnormalities, and the ILD did not progress. Anti-MDA5 antibody-positive dermatomyositis can be complicated by HPS.

Recurrence of anti-MDA5 antibody-positive clinically amyopathic dermatomyositis after long-term remission: A case report.

RATIONALE: Among all dermatomyositis (DM) patients, antimelanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) positive patients have significantly poor short-term mortality, whereas they experience less relapses over the long term after the remission. We report the case of a patient with anti-MDA5 Ab-positive clinically amyopathic dermatomyositis (CADM) with the recurrence of interstitial lung disease (ILD) after 7 years of remission. There has been no case report of an anti-MDA5 Ab-positive DM patient with the recurrence of ILD after 7 years of long-term remission. PATIENT CONCERNS: A 70-year-old Japanese woman was diagnosed with anti-MDA5 Ab-positive CADM and ILD. After achieving 7 years long-term remission, she was admitted to our department with erythema on the fingers and interstitial pneumonia. Her anti-MDA5 Ab titer was elevated. DIAGNOSES: We diagnosed recurrent CADM complicated with ILD. INTERVENTIONS: We successfully treated her with 1,000 mg of methyl-prednisolone pulse and intravenous cyclophosphamide therapy followed by prednisolone 50 mg/day and an increase of cyclosporine. OUTCOMES: After that treatment, the patient's skin symptoms and interstitial pneumonia were relieved. All laboratory investigations such as ferritin, the serum markers of interstitial pneumonia (i.e., SP-A, SP-D), and the titer of anti-MDA5 Ab showed signs of improvement. LESSONS: Her case suggests that careful physical examinations and monitoring the serum markers are important even after long-term remission is achieved.

Effect of a gonadotropin-releasing hormone analog for ovarian function preservation after intravenous cyclophosphamide therapy in systemic lupus erythematosus patients: a retrospective inception cohort study.

OBJECTIVE: To determine the effect of leuprolide acetate, a synthetic gonadotropin-releasing hormone analog (GnRH-a) on ovarian function preservation in systemic lupus erythematosus (SLE) patients treated with cyclophosphamide (CYC) in clinical practice. METHODS: We enrolled 30 premenopausal female SLE patients who fulfilled the 1997 American College of Rheumatology revised criteria and were treated with intravenous CYC (IVCY) in 2008-2017. We used Kaplan-Meier survival estimates to compare the GnRH-a-treated patients and those not treated with GnRH-a as controls. We performed Cox regression analyses to identify factors associated with premature ovarian failure (POF), incidences of cardiovascular events, strokes and osteoporosis after IVCY therapy. RESULTS: After a mean follow-up of 41 months, POF developed in one of the 16 GnRH-a-treated patients (6%) versus seven of the 14 controls (50%). Significantly improved cumulative ovarian protection over time was observed in the GnRH-a-treated group (P = 0.030). The hazard model analysis showed that treatment with GnRH-a during IVCY therapy is an independent factor associated with POF after IVCY therapy (adjusted hazards ratio = 0.12, 95% CI 0.01-0.67, P = 0.013) but not incidences of cardiovascular events, strokes or osteoporosis. CONCLUSION: The combined use of GnRH-a with IVCY therapy was associated with a significant reduction of POF among premenopausal women with SLE, suggesting that the addition of GnRH-a can be a strategy to prevent POF among premenopausal women with SLE after IVCY therapy.

Reversible Cognitive Dysfunction in Elderly-onset Systemic Lupus Erythematosus, Successfully Treated with Aggressive Immunosuppressive Therapy.

A 70-year-old Japanese woman presented to our hospital with gait disturbance and cognitive dysfunction. Since she had arthritis, lymphopenia, hypocomplementemia, and anti-nuclear and anti-double-stranded DNA antibodies, she was diagnosed with systemic lupus erythematosus (SLE). T2-weighted magnetic resonance imaging revealed bilateral hyperintensities in the putamen. Based on her cognitive impairment, muscle rigidity, and high levels of interleukin-6 in the cerebrospinal fluid, we believed she had developed a complication of a neuropsychiatric disease and administered corticosteroids and intravenous cyclophosphamide therapy. Her cognitive function fully recovered, and her gait disturbance improved. Attending to cognitive impairment in elderly SLE patients is necessary.

Successful treatment of plasma exchange for rapidly progressive interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis: A case report.

RATIONALE: As the initial treatment of rapidly progressive interstitial lung disease (RPILD) with antimelanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) patients, a combination of corticosteroids, cyclophosphamide, and calcineurin inhibitor is recommended. However, some of these patients have poor prognoses despite such intensive treatment. Other more effective treatments are desired. We report the case of an anti-MDA5 Ab-positive DM patient who had developed RPILD despite intensive treatments; she was treated successfully by a short-term plasma exchange (PE). PATIENT CONCERNS: A 71-year-old Japanese woman was admitted to the rheumatology department of another hospital with progressive muscle weakness of the limbs and erythema on both upper eyelids and the fingers of both hands. She was suspected of having classical DM (CDM) based on the findings of typical skin and myositis. Although a chest computed tomography (CT) examination showed no findings of interstitial pneumonia at the first visit to the department, she newly presented interstitial pneumonia during her admission and her anti-MDA5 Ab titer was elevated. DIAGNOSES: She was diagnosed with interstitial lung disease (ILD) with anti-MDA5 Ab-positive DM. INTERVENTIONS: She was treated with 1000 mg of methyl-prednisolone pulse, 500 mg of intravenous cyclophosphamide therapy (IVCY) followed by prednisolone 40 mg/day with tapering, and oral cyclosporine 200 mg/day. However, her interstitial pneumonia worsened with increasing breathing difficulty and an increasing serum ferritin level. She was transferred to our department, and we initiated PE as an additional treatment. OUTCOMES: After the PE treatment, all laboratory findings, for example, ferritin, KL-6, and the titer of anti-MDA5 Ab showed marked improvement, and the patient's skin symptoms and active interstitial pneumonia were relieved. LESSONS: Our patient's case suggests that PE may be effective for RPILD in anti-MDA5 Ab-positive DM patients.

Rituximab-induced Acute Thrombocytopenia in Granulomatosis with Polyangiitis.

A 72-year-old Japanese woman diagnosed with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis was admitted to our hospital with hearing loss, temporal pain, and sudden blindness. We finally diagnosed recurrent granulomatosis with polyangiitis and initiated methyl-prednisolone pulse therapy (1,000 mg) followed by prednisolone (30 mg/day) and rituximab (RTX). After the third RTX administration, she developed bloody stools along with acute thrombocytopenia and low complement levels. We diagnosed rituximab-induced acute thrombocytopenia (RIAT), and her platelet counts spontaneously recovered. This case suggests that after RTX therapy RIAT may sometimes cause severe thrombocytopenia, and that monitoring the complements may be useful for making an early diagnosis of RIAT.

Open-heart surgery without homologous blood transfusion in infants and children under simple deep hypothermia.

PURPOSE: To investigate the hematological changes during the perioperative period of open-heart surgery without homologous blood transfusion under simple deep hypothermia in infants and small children, and to define the limits of body weight for open-heart surgery without homologous blood transfusion under simple deep hypothermia. METHODS: We performed open-heart surgery without homologous blood transfusion under simple deep hypothermia on eight children, four infants, and a neonate with diagnoses of atrial septal defect, ventricular septal defect, on total anomalous pulmonary venous return (TATVR). All patients except for one with TAPVR were surface-cooled with ice water under deep ether anesthesia. Hematological examinations were performed seven times during the perioperative period. RESULTS: The body weight of the patients ranged from 2.5 to 15.0 kg (mean±SD, 9.5±3.5 kg) and the blood loss from 0.7 to 7.1g·kg-1 (4.6±2.0g·kg-1) The lowest values of the hematological findings in each case after surgery were as follows: Hb ranged from 7.6 to 10.9g·dl-1 (8.8±1.0g·dl-1), blood platelet count from 158×103 to 337×103 cells·µâ„“-1-agonist (271±88 ×103 cells·µâ„“-1-agonist, and total protein from 4.3 to 5.5 g·dl-1 (5.0±0.4g·dl-1) CONCLUSION: Severe anemia and hypoproteinemia were not detected in any case, and, in particular, the reduction of the platelet count was slight. No events occurred as a result of decreased Hb concentration, serum protein, or both.