Effective Maintenance Leukocytapheresis for Patients with Steroid Dependent or Resistant Ulcerative Colitis

Abstract: We prospectively examined the effect of leukocytapheresis (LA) on the maintenance of remission in 7 patients with ulcerative colitis (UC) who were initially refractory to corticosteroid therapy (steroid resistant or steroid dependent). The patients with refractory UC had been in remission due to LA (induction LA) in combination with the steroid therapy. They were then treated with LA once or twice a month for the purpose of maintaining remission (maintenance LA). The maintenance LA was performed by either a centrifuge method in 5 patients or a polyester adsorbent column method in 2 patients. Steroid dosage was gradually tapered as little as possible without recurrence based on clinical and/or colonoscopical judgments. Four patients were maintained in remission without steroids over 12 months. Recurrence was observed in 3 patients at 3, 3, and 6 months after the beginning of the maintenance LA, respectively. Two of the 3 patients were again conducted to remission by the second induction LA and maintained in remission by the second maintenance LA. Two patients finally underwent total colectomy because of recurrence of UC in a severe form. It is concluded that the maintenance LA therapy might be effective in some patients with steroid dependent or resistant UC for the maintenance of remission without steroids.     

Treatment for Churg-Strauss syndrome: induction of remission and efficacy of intravenous immunoglobulin therapy.

Churg-Strauss syndrome (CSS) is characterized by the presence of asthma, eosinophilia, and small-vessel vasculitis with granuloma. It is a distinct entity, as determined from all classifications of systemic vasculitis. The poor prognostic factors in CSS are renal insufficiency, cardiomyopathy, severe gastrointestinal (GI) tract, and central nervous systems (CNS) involvement. The initial management of CSS should include a high dose of a corticosteroid: prednisone at 1 mg/kg/day or its equivalent for methylprednisolone with tapering over 6 months. In patients with severe or rapidly progressing CSS, the administration of methylprednisolone pulse at 1 g/body/day for 3 days is recommended. When corticosteroid therapy does not induce remission, or when patients have poor prognostic factors, immunosuppressive cytotoxic therapy is indicated. However, some patients with severe CSS often show resistance to conventional treatment. We think that IVIG therapy is a hopeful candidate for second-line treatment for CSS patients, particularly in the case of neuropathy and/or cardiomyopathy, which are resistant to conventional therapy. However, there is not much evidence supporting the effectiveness of IVIG in CSS, and the mechanisms underlying the action of IVIG remain unclear. Now we are performing clinical trials of IVIG therapy for CSS patients who are resistant to conventional treatment, through a nationwide double-blinded placebo-controlled study in Japan.     

Treatment of refractory juvenile dermatomyositis with tacrolimus

We report the clinical course of three patients with refractory juvenile dermatomyositis (JDM) who were treated with tacrolimus. All three children had extensive skin disease and severe muscle weakness and were corticosteroid dependent. All three patients showed impressive improvement of mainly the cutaneous lesions. Furthermore, overall disease activity decreased, all children became more physically active, and corticosteroid treatment could be tapered. However, none of the patients showed recovery of muscle strength, which was most likely due to irreversible muscle damage related to the long-standing myositis and/or high-dose steroid treatment. Patients were followed up for 7 to 9 months after the introduction of tacrolimus. No adverse effects were seen. These cases demonstrate that tacrolimus has beneficial effects in children with refractory JDM, especially in those with severe cutaneous manifestations.     

Bisphosphonates in juvenile dermatomyositis with dystrophic calcinosis

Abstract

Objectives. Our primary objective was to retrospectively analyze whether bisphosphonates initiated in combination with immunosuppressive drugs and/or intravenous immunoglobulin (IVIG) resulted in a radiological and clinical improvement of dystrophic calcinosis in six female juvenile dermatomyositis (JDM) patients.

Methods. Medical records of the patients were reviewed. All six patients met the Bohan and Peter diagnostic criteria for JDM.

Results. A resolution of calcinosis was observed in four of the six patients with JDM following the use of bisphosphonates and intensive immunosuppressive therapy with or without IVIG. Bisphosphonates were unable to either decelerate the progression of calcinosis or improve calcinosis in cases 5 and 6. In case 5, it took a relatively long time to control the disease activity despite the appropriate immunsuppressive treatment and she experienced multiple flares of active JDM. Case 6 had a long duration of severe active disease before treatment initiation. No important adverse event was observed.

Conclusions. Early commencement of aggressive immunosuppressive agents in combination with bisphosphonate is a choice for the treatment of calcinosis in JDM patients. Concomitant use of IVIG may have an additional effect on the resolution of calcinosis.     

Inefficacy of intravenous immunoglobulin in patients with low-risk thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome.

OBJECTIVE: To assess the efficacy of intravenous immunoglobulin (IVIG), in comparison with plasma exchange (PE), in the treatment of patients with thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). DESIGN: Prospective, nonrandomized comparative study. SETTING: Hematology department in a general hospital. PATIENTS: 17 consecutive adult patients, six of them pregnant, with diagnosis of TTP/HUS. Three had a severity score at diagnosis less than or equal to 4 and were treated with IVIG and 14 had a severity score of greater than or equal to 5 and/or were pregnant and received PE. The response was evaluated after 5 days of therapy. RESULTS: Complete remission was obtained in 0/3 cases treated with IVIG and 10/14 (71%) with PE (Fisher's exact test P = 0.05). Three patients died for widespread TTP-HUS, and four had persistent disease. In three of the four resistant patients, complete remission was obtained by further PE but not by further IVIG. The overall remission rate was 76% (13/17). CONCLUSIONS: Our study does not confirm the utility of IVIG in the management of TTP-HUS, as suggested by earlier single case reports.     

Intravenous Immunoglobulin Therapy for Refractory Interstitial Lung Disease Associated with Polymyositis/Dermatomyositis

Interstitial lung disease (ILD) associated with polymyositis/dermatomyositis (ILD-PM/DM), including amyopathic dermatomyositis (ADM), is recognized as an important condition because it frequently causes death, despite intensive therapy with high-dose corticosteroid and immunosuppressive agents, such as cyclosporine A and cyclophosphamide. Intravenous immunoglobulin therapy (IVIG) has shown efficacy for myopathy associated with PM/DM, but its usefulness for ILD-PM/DM is unclear. This study was designed to investigate the efficacy of IVIG for refractory ILD-PM/DM. A review was made of medical charts of five patients (2 men and 3 women) who were treated with IVIG for refractory ILD-PM/DM resistant to high-dose corticosteroid and cyclosporine A and/or cyclophosphamide. One patient had acute ILD-PM and four patients had acute ILD-ADM. Of the five patients, one patient with ILD-PM and one patient with ILD-ADM survived. No adverse reactions were seen due to IVIG treatment. There were no critical differences in the clinical parameters and clinical courses between survivors and nonsurvivors. IVIG treatment is safe and could be an effective salvage therapy for refractory ILD-PM/DM in certain cases, suggesting that further controlled trials are worthwhile.     

Treatment of polyarteritis nodosa and microscopic polyangiitis without poor‐prognosis factors: A prospective randomized study of one hundred twenty‐four patients

Objective

To assess the efficacy of systemic corticosteroids alone as first‐line treatment of polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA) without poor‐prognosis factors as defined by the Five‐Factors Score (FFS), and to compare the efficacy and safety of azathioprine versus pulse cyclophosphamide as adjunctive immunosuppressive therapy for patients experiencing treatment failure or relapse.

Methods

This prospective, multicenter, therapeutic trial included 124 patients with newly diagnosed PAN or MPA (FFS of 0) treated with corticosteroids alone. At the time of treatment failure or disease relapse, patients were randomized to receive 6 months of therapy with oral azathioprine or 6 pulses of cyclophosphamide. Analyses was performed according to an intent‐to‐treat strategy.

Results

The mean ± SD followup period was 62 ± 33 months. Treatment with corticosteroids alone induced remission in 98 patients; 50 (40%) of these patients had sustained disease remission, 46 (37%) experienced a relapse, and 2 became corticosteroid dependent (daily prednisone dose ≥20 mg). In 26 patients (21%), treatment with corticosteroids alone failed, and 49 patients (40%) required additional immunosuppression. Among the 39 patients randomized, 13 of 19 achieved remission with cyclophosphamide pulses, and 14 of 20 achieved remission with azathioprine. Among all patients, the 1‐year and 5‐year survival rates were 99% and 92%, respectively. Six deaths occurred in the cyclophosphamide‐treated group compared with 2 deaths in the azathioprine‐treated group. Disease‐free survival was significantly lower for patients with MPA than for those with PAN (P = 0.046).

Conclusion

For patients with PAN or MPA with an FFS of 0, overall 5‐year survival was good, but first‐line corticosteroid treatment was able to achieve and maintain remission in only about half of the patients, and 40% of the patients required additional immunosuppressive therapy. Azathioprine or pulse cyclophosphamide was fairly effective for treating corticosteroid‐resistant disease or major relapses.

     

Low dose cyclosporine A in the treatment of resistant proliferative lupus nephritis

Objective: This study aimed to evaluate long-term efficacy of low dose cyclosporine A (CsA) in the treatment of resistant proliferative lupus nephritis.

Methods: In this retrospective study, patients with biopsy proven proliferative lupus nephritis who were unresponsive to combination therapy with steroid plus mycophenolate mofetil (MMF) or cyclophosphamide (CYC) and had been treated with CsA were included. Efficacy monitoring was based on the systemic lupus erythematosus (SLE) disease activity index, dose of prednisolone, serum complement, anti–double stranded DNA (anti-dsDNA) titration, urine analysis, proteinuria, creatinine clearance, remission of the renal disease, renal survival and involvement of other organs.

Results: This study included 27 consecutive patients (22 females, 5 males) with resistant proliferative lupus nephritis. Mean duration of follow up and treatment with CsA were 40.7?±?24.9 and 35.2?±?19.1 months, respectively. Complete and partial renal remission occurred in 66.9% and 25.7% patients, respectively. Creatinine clearance was stable, proteinuria and anti-dsDNA titer decreased, and C3 and C4 increased significantly during the treatment with CsA. Severe complications such as death, dialysis, kidney transplantation and severe infection did not occur in the studied patients during the follow-up period.

Conclusions: Low-dose CsA could induce renal remission and ameliorate the SLE disease activity in patients with resistant proliferative lupus nephritis and it would be a safe drug for treatment of these patients.     

Prior bowel resections,perianal disease,and a high initial Crohn's disease activity index are associated with corticosteroid resistance in active Crohn's disease

OBJECTIVES: Some patients with Crohn's disease (CD) do not respond to corticosteroid therapy. Furthermore, corticosteroids frequently cause side effects. Thus, predictive parameters for treatment refractoriness would be helpful for treatment decisions. METHODS: A total of 300 patients with active CD (i.e., with a Crohn's Disease Activity Index [CDAI] >200) entered the study. Treatment started with 60-100 mg/day prednisolone equivalent, which was then tapered to 10-15 mg/day within 6 wk and maintained at that dose for another 4 wk. After 10 wk of treatment, response to steroids was defined by a CDAI <150, steroid resistance by a CDAI always > or =150 and steroid dependency by a relapse after dose reduction. Of 239 eligible patients, 196 were responders, 26 were steroid resistant, and 17 were steroid dependent. RESULTS: Prior bowel resections, a high initial CDAI, and perianal disease were associated with steroid resistance. Of the steroid resistant patients 53.9% were bowel-resected compared to 20.4% of the responders (relative risk = 3.63; 95% CI = 1.79-7.36). Perianal disease was observed in 42.3% of steroid resistant patients versus 21.9% of responders (relative risk = 2.28; 95% CI = 1.12-4.66) and initial CDAI was 347+/-91 in resistant patients versus 301+/-81 in responders (p < 0.05). Parameters for steroid dependent patients were not significantly different from those of responders. CONCLUSIONS: In this study (thus far the largest study for the evaluation of predictive factors for treatment refractoriness to corticosteroids in CD), only prior bowel resection, perianal disease, and a high initial CDAI were found to be predictive of resistance to steroid treatment.     

Enzyme elevation in patients with juvenile dermatomyositis and steroid myopathy

OBJECTIVE: Steroid myopathy can occur in patients with juvenile dermatomyositis (JDM) receiving chronic steroid therapy. We report an elevation of serum muscle enzymes, normal strength by manual muscle testing (MMT), and electromyographic (EMG) findings of steroid myopathy in children with JDM. METHODS: We prospectively studied children with JDM with a history of chronic steroid use (> 3 mo) and ongoing inflammatory myositis who were referred to our institution. RESULTS: We identified 5/9 children with JDM receiving longterm high dose steroids who had muscle enzyme elevation with no definable weakness and EMG findings consistent with steroid myopathy. All subjects improved after withdrawal of their steroid therapy. CONCLUSION: Longterm high dose steroids may lead to steroid myopathy with muscle enzyme elevation, previously reported only with acute steroid myopathy. We recommend that muscle derived enzyme levels should not be used to differentiate steroid myopathy from inflammatory myopathies.     

Intravenous gammaglobulin treatment for immune thrombocytopenia associated with infectious mononucleosis

Severe thrombocytopenia is an uncommon (incidence less than 1%) but serious complication of infectious mononucleosis. Corticosteroids have been used for therapy with variable responses reported. Five consecutive patients with infectious mononucleosis-related severe thrombocytopenia were treated with intravenous gammaglobulin (IVIG) at a dose of 400 mg/kg/day for 2-5 days. All patients appear to have had an immunologic or consumptive etiology for their thrombocytopenia as determined by increased marrow megakaryocytes. All patients were initially treated with oral prednisone 1 mg/kg/day. Due to the relatively slow response to prednisone (platelet count less than 20,000/microliters on the 8th to 13th hospital day) or increased bleeding symptoms, IVIG was initiated. Four of the five patients rapidly developed significant increases in their platelet counts (range 44,000/microliters to 97,000/microliters). Two of these responses were sustained and two relapses occurred (while on continued steroid therapy) which again responded to booster doses of IVIG at similar doses. IVIG has been previously shown to be effective in treating patients with idiopathic thrombocytopenia purpura. Historically, patients with infectious mononucleosis-related severe thrombocytopenia often are refractory to corticosteroid therapy and our limited experience suggests that IVIG may also be effective in infectious mononucleosis-related severe thrombocytopenia.     

Bone mineral density in children and adolescents with systemic lupus erythematosus, juvenile dermatomyositis, and systemic vasculitis: relationship to disease duration, cumulative corticosteroid dose, calcium intake, and exercise

OBJECTIVE: To describe the frequency of abnormal bone mineralization in a population of children with juvenile systemic lupus erythematosus (JSLE), juvenile dermatomyositis (JDM), and systemic vasculitis; and to investigate the relationship of bone mineral density (BMD) to cumulative corticosteroid dose, disease duration, Tanner stage, calcium intake, and exercise in these patients. METHODS: A retrospective chart review of children attending the pediatric rheumatology clinic at British Columbia's Children's Hospital was conducted to obtain demographic data (sex, ethnicity, disease duration, cumulative corticosteroid dose, and mean daily corticosteroid dose). All patients had at least one BMD measurement by dual energy x-ray absorptiometry (DEXA) at lumbar spine, hip, and total body. BMD was expressed as g/cm2 and Z scores; an abnormal Z score was defined as 相似文献   

Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systematic literature review

The objectives of this study are to review and summarize published information on the use, effectiveness, and adverse effects of intravenous immunoglobulin (IVIG) in patients with polymyositis (PM) or dermatomyositis (DM) and to search MEDLINE and CNKI (Chinese) databases from 1985 to 2011 to retrieve clinical research articles concerning IVIG in adult patients with PM/DM. Of the 14 articles selected, two were randomized controlled trials, nine prospective open studies, and three retrospective studies with a total of 308 adult patients. IVIG has been used successfully in the treatment of PM/DM. The standard dose is 2 g/kg, given in two to five individual daily doses. The course of IVIG treatment is usually 3~6 months. IVIG therapy seemed rarely employed as first-line therapy in PM/DM. In a double-blind study conducted in patients with refractory DM, IVIG combined with corticosteroid significantly improved muscle strength and decreased serum creatine kinase level, compared with placebo. The beneficial effect of IVIG in refractory, flare-up, rapidly progressive, or severe PM/DM has been documented in many open-label trials. IVIG was shown to be effective in most of PM/DM patients with lung involvement and esophageal involvement. In some patients, IVIG can lower the corticosteroid dose required for maintenance, demonstrating the most effective steroid-sparing effect. Adverse effects were generally tolerable. IVIG is effective in the treatment of adult patients with PM/DM and appears to be relatively well tolerated and safe. IVIG may be a good choice especially in patients with refractory, flare-up, rapidly progressive, or severe PM/DM, and can be tried in patients with a contraindication for corticosteroid.     

Kawasaki disease: 40 years after the original report

The cause of Kawasaki disease (KD) remains unknown, although a number of epidemiologic and clinical observations suggest it is triggered by one or more infectious agents, each of which can result in the clinical manifestation of the disease. Advances have been made in the management of the disease with the introduction of aspirin and intravenous immunoglobulin (IVIG), which have had a significant impact on lowering the rate of coronary artery aneurysms and death from the disease. Questions remain regarding the management of those patients who fail to respond to IVIG. It appears that some patients with severe KD who are resistant to IVIG may benefit from IV pulse steroid therapy or infliximab infusion. However, a recent multicenter, randomized, controlled trial did not support the addition of a pulsed dose of intravenous methylprednisolone to the conventional IVIG therapy for the primary treatment of KD. It remains to be seen whether other anti-inflammatory agents such as immunosuppressive therapies or new biologics will play a role in the management of patients with KD.     

Efficacy and safety of rituximab in adults' warm antibody autoimmune haemolytic anemia: Retrospective analysis of 27 cases

To better assess the efficacy and safety of rituximab in adults' warm antibody autoimmune hemolytic anemia (wAIHA), we conducted a retrospective study including 27 adults (mean age 49.7 ± 21 years) with either primary (n = 17) or secondary (n = 10) wAIHA. On average, the patients received 2.1 ± 1.4 treatment lines before rituximab and six had undergone splenectomy. Five patients were resistant to corticosteroids, 16 had a corticosteroid‐dependent wAIHA and six had relapsed after an initial remission. Overall, 25/27 (93%) patients achieved an initial response from rituximab (eight complete responses and 17 partial responses). During a mean follow‐up of 20.9 months after rituximab, five of the responders relapsed, three of whom were successfully retreated with rituximab. Two mild infusion‐related‐reactions occurred, one patient had a rituximab‐related severe neutropenia and one case of pneumocystis jiroveci pneumonia occurred in a severely immunocompromized patient. In conclusion, rituximab seems highly effective and relatively safe in adults with steroid‐resistant or steroid‐dependent wAIHA. Am. J. Hematol. 2009. © 2008 Wiley‐Liss, Inc.     

Intravenous immunoglobulins for steroid‐refractory esophageal involvement related to polymyositis and dermatomyositis: A series of 73 patients

Objective

To assess the long‐term outcome of esophageal complications in the group of patients receiving intravenous immunoglobulins (IVIG) for the treatment of severe steroid‐refractory esophageal involvement related to polymyositis/dermatomyositis (PM/DM).

Methods

We retrospectively reviewed the medical records of 73 patients (39 with PM, 34 with DM) with steroid‐resistant esophageal involvement. Esophageal involvement was evaluated by clinical and manometric investigations.

Results

Seventy‐three patients with steroid‐refractory esophageal involvement related to PM/DM received IVIG therapy (2 gm/kg monthly). The median interval between PM/DM diagnosis and the onset of esophageal complications was 6 months. The most common clinical manifestations revealing esophageal dysfunction were dysphagia (69.9%), coughing while eating (61.6%), and gastroesophageal reflux into the pharynx and/or mouth (34.2%). Twenty‐five patients exhibited life‐threatening esophageal complications requiring exclusive enteral feeding; 33 patients (45.2%) with esophageal impairment developed aspiration pneumonia. Sixty patients (82.2%) exhibited resolution of esophageal clinical manifestations, leading to a return to normal oral feeding and ablation of feeding enteral tubes. Four other patients (5.5%) improved, although they still experienced mild dysphagia intermittently. Because of impaired cricopharyngeal muscle relaxation, another patient successfully underwent cricopharyngeal myotomy. Eight patients died from aspiration pneumonia (n = 6) and cancer (n = 2). Muscle weakness, thoracic myopathy, and aspiration pneumonia were independent predictive factors of IVIG‐treated esophageal complications in PM/DM patients.

Conclusion

Our findings indicate that IVIG should be considered in life‐threatening esophageal impairment complicating steroid‐resistant PM/DM. We also suggest that combined therapy of IVIG and high‐dose steroids may be the first‐line therapy in PM/DM patients with life‐threatening esophageal manifestations.     

Successful treatment with regimen of intravenous gamma globulin and cyclophosphamide for dermatomyositis accompanied by interstitial pneumonia, opportunistic infection and steroid psychosis.

BACKGROUND: A 47-year-old Japanese woman was suffering from dermatomyositis with progressive interstitial pneumonia, which was resistant to treatment with prednisolone (Pred) and cyclosporine A (CsA). Unfortunately, the opportunistic infection and steroid psychosis made therapeutic intervention using additional immunosuppressive drugs problematic. To overcome these difficulties, we created a regimen of intravenous gammaglobulin (IVIG) and cyclophosphamide (CPM) for the treatment of this patient. METHODS: For the simultaneous treatment, IVIG-CPM was added to Pred/CsA by means of infusion of IVIG on five consecutive days per month, followed by CPM infusion on the ninth day after the last IVIG administration. The treatment was repeated for four months. RESULTS: This regimen induced almost full remission without exacerbation of the opportunistic infection or mental disturbance. CONCLUSIONS: The outcome reported here suggests that the combination therapy of Pred/CsA and IVIG-CPM appears to be useful for the treatment of dermatomyositis with pulmonary, infectious and mental complications.     

Clinical experience with biologic treatment in resistant eosinophilic fasciitis: Case reports and review of the literature

Rationale:Eosinophilic fasciitis (EF) is an uncommon connective tissue disorder characterized by limb and trunk erythema, with symmetrical thickening of the skin. Its pathogenesis is poorly understood. Treatment consists mainly of glucocorticoids. Yet, no randomized trials have evaluated therapies for this rare disease and the optimal treatment modality remains unclear. Although most patients show partial or complete response to glucocorticoids, many relapse upon drug tapering, while others either do not respond at all or fail to sustain prolonged remission. Second-line therapy for this rare disorder includes mainly methotrexate (MTX), azathioprine, cyclosporine and hydroxychloroquine. Recently, several attempts using rituximab and intravenous immunoglobulins (IVIG) have shown good clinical results.Patient concerns:The three patients had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. Adding methotrexate in all patients and azathioprine to patient 3 did not lead to remission.Diagnoses:EF was diagnosed in all patients based on clinical presentation accompanied by fascia biopsy that demonstrated eosinophilic fasciitis.Interventions:The patients were successfully treated with rituximab or IVIG, achieving sustained remission.Outcomes:The three cases had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. The patients were then successfully treated with rituximab or IVIG, achieving sustained remission.Lessons:This review of three cases of EF supports the results of previous reports, suggesting addition of rituximab and IVIG is an effective treatment for patients with refractory disease.     

Treatment of intravenous immunoglobulin-resistant Kawasaki disease with methotrexate

OBJECTIVE: To evaluate the effect of low-dose oral methotrexate (MTX) as treatment for patients with Kawasaki disease (KD) resistant to intravenous immunoglobulin (IVIG). METHODS: The subjects were four patients with KD, aged 8 months to 8 years old, who showed persistent disease after treatment with high-dose IVIG (2 g/kg) and aspirin (100 mg/kg). These patients were re-treated with IVIG and were also treated with IV dexamethasone (0.3 mg/kg). IV dexamethasone induced defervescence in three patients, but fever recurred upon discontinuing the steroid. One patient showed no response to either IVIG or dexamethasone. All patients were subsequently treated weekly with low-dose oral MTX [10 mg/body surface area (BSA)]. RESULTS: MTX treatment resulted in rapid defervescence, improvement in clinical symptoms, and normalization of acute-phase reactants in all patients. There was no progression of coronary artery dilatation and MTX was discontinued with no recurrence of fever. No adverse effects of MTX were observed. CONCLUSION: Low-dose oral MTX is an effective treatment for refractory KD.