Long-term Drug-free Remission Research Articles

HIGH LONG-TERM DRUG-FREE REMISSION RATE FOR ACUTE VOGT-KOYANAGI-HARADA DISEASE WITH AN APPROPRIATE IMMUNOSUPPRESSIVE REGIMEN.

To report the clinical profile and outcomes of acute Vogt-Koyanagi-Harada disease with a strict immunosuppression regimen and investigate the risk factors for a prolonged disease course. A total of 101 patients with acute Vogt-Koyanagi-Harada (202 eyes) with more than 24 months of follow-up were recruited from January 2011 to June 2020. They were divided into two groups according to the interval between the onset of Vogt-Koyanagi-Harada and treatment. Oral prednisone was gradually tapered off by a diminished dose according to a relatively strict protocol. Patient responses to the treatment regimen were classified as long-term drug-free remission or chronic recurrent. Ninety-six patients (95.0%) achieved long-term drug-free remission without recurrence, while 5 (5.0%) had chronic recurrence. Most patients achieved good best-corrected visual acuity (90.6% ≧20/25). A generalized estimation equation model demonstrated that time of visit, ocular complications, and cigarette smoking were independent risk factors for a longer disease course, and smokers required a higher drug dose and longer treatment course than nonsmokers. An immunosuppressive regimen with an appropriate tapering speed can lead to long-term drug-free remission in patients with acute Vogt-Koyanagi-Harada. Cigarette smoking significantly affects ocular inflammation.

Looking for the best strategy to treat children with new onset juvenile idiopathic arthritis: presentation of the “comparison of STep-up and step-down therapeutic strategies in childhood ARthritiS” (STARS) trial

BackgroundAlthough a satisfactory disease control is nowadays achievable in most patients with JIA, a substantial proportion of them still do not respond adequately or reach long-term drug-free remission. According to current recommendations, treatment should be escalated in subsequent steps. A different approach is based on the assumption that the initial start of an aggressive therapy may take advantage of the “window of opportunity” and could alter the biology of the disease, leading to an improvement of long-term outcomes, including the prevention of cumulative joint damage.ObjectivesThis randomised clinical trial aims to compare the effectiveness of a conventional therapeutic regimen, based on treatment escalation and driven by the treat-to-target approach, with that of an early aggressive intervention based on the initial start of a combination of conventional and biological DMARDs.MethodsJIA patients with oligoarthritis or RF negative polyarthritis aged more than 2 years and with less than 4 months of disease course will be included in the study. Children will be randomised into two arms: patients in Step-up arm with less severe oligoarthritis will undergo an intra-articular corticosteroid injection (IACI) in all affected joints; patients with polyarthritis or severe oligoarthritis will receive IACI and methotrexate. Subsequent treatment will follow a standardised protocol based on the patients’ level of disease activity measured with the JADAS, according to a treat-to-target strategy. Patients in Step-down arm will receive a 6-month early combined treatment (methotrexate plus IACI for less severe oligoarthritis, methotrexate plus etanercept for severe oligoarthritis and polyarthritis). The primary endpoint is the frequency of achievement of the status of clinical remission (i.e. persistence of inactive disease for at least 6 months) at the 12-month visit. Safety events, physician-centred measures and parent/patient-reported outcomes will be collected through the Paediatric Rheumatology International Trials Organisation on line database.Expected resultsThe STARS trial aims to provide important evidence supporting the first-line treatment choices in the care of children with oligoarticular and polyarticular JIA. If the superiority of an early aggressive therapy will be demonstrated, this will demand further studies on the biological definition of the window of opportunity for JIA.Trial registrationThe Trial is registered on the ClinicalTrials.gov registry (NCT03728478) on the 31st October 2018 and EU Clinical Trials Register on the 14th May 2018 (EudraCT Number: 2018–001931-27).

IgG Anti-Citrullinated Protein Antibody Variable Domain Glycosylation Increases Before the Onset of Rheumatoid Arthritis and Stabilizes Thereafter: A Cross-Sectional Study Encompassing ~1,500 Samples.

ObjectiveThe autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti–citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of N‐linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages.MethodsUsing liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new‐onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long‐term drug‐free remission (DFR) during up to 16 years follow‐up.ResultsIgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset.ConclusionThe abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre‐disease phase and contributes to disease development.

Трансплантация аутологичных гемопоэтических стволовых клеток c целью лечения активного анкилозирующего спондилита (клиническое наблюдение)

Nowadays, patients with ankylosing spondylitis (AS) receive drugs for an indefinite period of time, which determines the need to search for new types of treatment that can induce medium- and long-term drug-free remission. Some authors consider the possibility of autologous hematopoietic stem cell transplantation (aHSCT) in combination with high-dose chemotherapy as such methods of treatment. The evidence base on the efficacy and safety of aHSCT in AS is represented by single cases, one of which we are currently presenting. The article presents the results of a seven-year clinical follow-up concerning a male patient with severe AS who underwent aHSCT, which led to the achievement of short-term remission with subsequent disease exacerbation. Due to the high activity of AS and zero treatment result, it was decided to initiate treatment with the interleukin 17A (IL-17A) inhibitor, secukinumab. At the time of writing, the patient has been receiving secukinumab at a dose of 300 mg per month for 3 years. During the first year of treatment, there was a significant positive clinical and laboratory tendency in the form of a pain syndrome reduction, normalization of ESR and CRP levels, a decrease in the BASDAI index to 3.2 points, and the ASDAS index to 1.8 points. The authors conclude that aHSCT in combination with high-dose chemotherapy and subsequent administration of cyclosporine A in the presented case did not lead to persistent remission of AS, and the risk–benefit ratio for the patient is shifted towards risk. At the same time, treatment with IL-17A inhibitor in a standard dosage allowed to control the disease activity with a high safety profile for 3 years. KEYWORDS: ankylosing spondylitis, Bekhterev’s disease, radiographic axial spondyloarthritis, autologous hematopoietic stem cell transplantation, TNF-alpha inhibitors, IL-17A inhibitor, remission. FOR CITATION: Benevolenskaya S.S., Maslyansky A.L., Chudinov A.L. et al. Autologous hematopoietic stem cell transplantation for the treatment of active ankylosing spondylitis (clinical case). Russian Medical Inquiry. 2022;6(8):486–490 (in Russ.). DOI: 10.32364/2587- 6821-2022-6-8-486-490.

Adult-Onset Autoimmune Enteropathy in an European Tertiary Referral Center.

INTRODUCTION:Adult-onset autoimmune enteropathy (AIE) is a rare cause of severe chronic diarrhea because of small intestinal villous atrophy. We report on patients with adult-onset AIE in an European referral center.METHODS:Retrospective study including patients diagnosed with AIE in the Amsterdam UMC, location VUmc, between January 2003 and December 2019. Clinical, serological, and histological features and response to treatment were reported. The specificity of antienterocyte antibodies (AEA) was evaluated by examining the prevalence of AEA in (i) controls (n = 30) and in patients with (ii) AIE (n = 13), (iii) celiac disease (CD, n = 52), (iv) refractory celiac disease type 2 (n = 18), and (v) enteropathy-associated T-cell lymphoma (EATL, n = 10).RESULTS:Thirteen AIE patients were included, 8 women (62%), median age of 52 years (range 23–73), and 6 (46%) with an autoimmune disease. AEA were observed in 11 cases (85%), but were also found in CD (7.7%), refractory celiac disease type 2 (16.7%), and EATL (20%). Ten patients (77%) were human leukocyte antigen DQ2.5 heterozygous. Total parenteral nutrition was required in 8 cases (62%). Steroids induced clinical remission in 8 cases (62%). Step-up therapy with rituximab, cyclosporine, infliximab, and cladribine in steroid-refractory patients was only moderately effective. Four patients died (31%), but 4 (31%) others are in long-term drug-free remission after receiving immunosuppressive treatment, including 1 patient who underwent autologous stem cell transplantation.DISCUSSION:Adult-onset AIE is a rare but severe enteropathy that occurs in patients susceptible for autoimmune disease. Four patients (31%) died secondary to therapy-refractory malabsorption, while immunosuppressive therapy leads to a long-lasting drug-free remission in one-third of patients.

Rheumatoid arthritis: Moving towards IMPROVED drug-free remission.

The newly published 5-year outcomes of the IMPROVED trial demonstrate the feasibility of achieving long-term drug-free remission in early rheumatoid arthritis (RA). These findings raise the bar and support the use of a remission induction and maintenance approach, particularly in patients presenting with early joint inflammation consistent with early RA.

Long-Term Drug-Free Remission and Visual Outcomes in Sympathetic Ophthalmia

ABSTRACTPurpose: To assess corticosteroid- and immunosuppressive therapy (IST)-free long-term remission in the treatment of patients with sympathetic ophthalmia (SO), a vision-robbing disease that can span a lifetime.Methods: The medical records of 19 patients with SO aged 16.1 to 94.95 years (median age 58.56 years) with median follow-up of 7.10 years (mean, 6.41; range, 2.5 to 8.63 years) were retrospectively examined.Results: All patients achieved control of inflammation, 13 of them for 2 years or more. Three (15.78%) of the 19 patients maintained remission without IST and corticosteroids for more than 5 years with vision of 20/25 or better in the sympathizing eye. Thirteen patients (68.42%) were inactive on IST or corticosteroids or in combination therapy. Eleven patients (57.9%) maintained visual acuity of 20/40 or better at the end of follow-up.Conclusion: Even with a devastating and possibly lifelong disease like sympathetic ophthalmia, long-term remission off all IST and corticosteroids, and perhaps even cure, is possible.

Short-Term Continuous Subcutaneous Insulin Infusion Combined with Insulin Sensitizers Rosiglitazone, Metformin, or Antioxidant α-Lipoic Acid in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

Short-term continuous subcutaneous insulin infusion (CSII) in patients with newly diagnosed type 2 diabetes has been proved effective in improving metabolic control and β-cell function, thus inducing long-term drug-free remission. A randomized controlled trial was conducted to investigate whether CSII in combination with rosiglitazone, metformin, or α-lipoic acid separately brings about extra benefits. One hundred sixty patients with newly diagnosed type 2 diabetes were randomized to one of four treatment groups: CSII alone, CSII in combination with rosiglitazone or metformin for 3 months, or CSII with α-lipoic acid intravenous infusion for 2 weeks. Duration of CSII treatment was identical in the four groups. Glucose and lipid profiles, homeostasis model assessment (HOMA) indices, acute insulin response (AIR), intramyocellular lipid (IMCL) level, and malondialdehyde level were compared before and after intervention. The near-normoglycemia rate at the third month in CSII alone and that in combination with rosiglitazone, metformin, or α-lipoic acid was 72.5%, 87.5%, 90%, and 75%, respectively (metformin group vs. CSII alone, P=0.045). The metformin group achieved euglycemia in a shorter time (2.6 ± 1.3 vs. 3.7 ± 1.8 days, P=0.020) with less daily insulin dosage and was more powerful in lowering total cholesterol, increasing AIR and HOMA β-cell function, whereas reduction of IMCL in the soleus was more obvious in the rosiglitazone group but not in the metformin group. The efficacy of combination with α-lipoic acid was similar to that of CSII alone. Short-term CSII in combination with rosiglitazone or metformin is superior to CSII alone, yet the efficacy of the two differs in some way, whereas that with α-lipoic acid might not have an additive effect.

Dendritic cells and the promise of antigen-specific therapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disease resulting from an autoimmune response to self-antigens, leading to inflammation of synovial tissue of joints and subsequent cartilage and bone erosion. Current disease-modifying anti-rheumatic drugs and biologic inhibitors of TNF, IL-6, T cells and B cells block inflammation nonspecifically, which may lead to adverse effects, including infection. They do not generally induce long-term drug-free remission or restoration of immune tolerance to self-antigens, and lifelong treatment is usual. The development of antigen-specific strategies in RA has so far been limited by insufficient knowledge of autoantigens, of the autoimmune pathogenesis of RA and of the mechanisms of immune tolerance in man. Effective tolerance-inducing antigen-specific immunotherapeutic strategies hold promise of greater specificity, of lower toxicity and of a longer-term solution for controlling or even preventing RA. This paper reviews current understanding of autoantigens and their relationship to immunopathogenesis of RA, and emerging therapeutics that aim to leverage normal tolerance mechanisms for implementation of antigen-specific therapy in RA.

Management of ocular mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is an immune-mediated systemic disease affecting the mucosa of the mouth, eyes, nasopharynx, GI tract, genitalia and skin. Chronic inflammation and subepithelial blisters of the mucosa result in progressive scarring. Ocular MMP is characterized by a chronic cicatrizing conjunctivitis, which leads to symblepharon, entropion, trichiasis, severe dry eye, cornea ulceration and potential blindness when untreated. One of the most effective treatments for ocular MMP is the combination therapy of cyclophosphamide (administered for 12–18 months) and oral corticosteroids (tapered over 3–4 months). This regimen has proven effective in controlling conjunctival inflammation, halting mucosal scarring and preventing potential vision loss, and is typically used for severe disease. Long-term drug-free remission is achievable in patients with this regimen. For all immunosuppressive medications, careful monitoring for drug-related side effects is crucial.

Attitudes Toward Diabetes Affect Maintenance of Drug-Free Remission in Patients With Newly Diagnosed Type 2 Diabetes After Short-Term Continuous Subcutaneous Insulin Infusion Treatment

OBJECTIVEShort-term intensive insulin treatment in patients with newly diagnosed type 2 diabetes can improve β-cell function and insulin sensitivity, which results in long-term remission without need for further antidiabetes medication. Patient attitudes toward their disease were assessed using the Diabetes Care Profile (DCP) tool to evaluate the potential impact on maintaining long-term remission.RESEARCH DESIGN AND METHODSNewly diagnosed patients with type 2 diabetes were recruited and treated with continuous subcutaneous insulin infusion (CSII) for 2–3 weeks. They were also invited to participate in diabetes self-management intervention during hospitalization and complete a DCP questionnaire on attitudes toward diabetes at baseline and 3, 6, and 12 months after suspension of CSII.RESULTSNear normoglycemia was achieved by 118 patients after short-term CSII, with 65 remaining in drug-free remission for >1 year. They had significantly better glycemic control and greater restoration of acute insulin response after CSII as well as higher educational attainment compared with patients experiencing relapse. They also achieved higher scores in positive attitude, (belief in) importance of care, care ability, self-care adherence, and less negative attitude. Differences between the two groups became greater over time. Cox proportional hazards model analysis indicated that greater self-care adherence (hazard ratio 0.184, P < 0.001) and homeostasis model assessment of insulin resistance before treatment (0.854, P = 0.053) were independent predictors for long-term remission, whereas elevated 2-h postprandial plasma glucose after CSII (1.156, P = 0.015) was a risk factor for relapse.CONCLUSIONSAttitudes toward diabetes affect long-term drug-free remission in newly diagnosed patients with type 2 diabetes after short-term CSII.

Treatment of Acne Vulgaris and Prevention of Acne Scarring: Canadian Consensus Guidelines

Acne affects approximately 95% of the population at some point during their lifetime.1 This common disorder can range from mild to severe forms, cause sometimes extensive scarring, and can last well into the fourth and fifth decades. Effective therapeutic agents are available to both treat acne and prevent ongoing disease. Despite this, dermatologists frequently see patients with significant acne scarring because many patients delay seeking medical attention for acne and many practitioners procrastinate over using effective antiscarring options. In patients who already demonstrate scarring, repeated courses of antibiotics only result in recurring acne and additional scarring. This, in turn, exacerbates the despair and other adverse psychosocial effects of the disease. There are a variety of agents and devices to help acne patients with scarring. However, successful treatment cannot be guaranteed, and in most cases residual scarring will be evident. Thus, the most effective way of managing acne scarring is to prevent its occurrence in the first place. Although we currently have a number of effective antiacne agents to control the disease, such as antibiotics and hormonal agents, isotretinoina is the only agent that has been shown to induce long-term drug-free remission and curative potential.