The JAK/STAT signaling pathway: from bench to clinic | Signal Transduction and Targeted Therapy
Covid-19 Linked To Higher Risk Of Developing Autoimmune Inflammatory Rheumatic Diseases
OLDHAM, UNITED KINGDOM - NOVEMBER 24: A man wearing a protective face mask walks past an ... [+] illustration of a virus outside Oldham Regional Science Centre on November 24, 2020 in Oldham, United Kingdom. England is continuing its second national coronavirus lockdown. People are still permitted to exercise with one other person, takeaway food is permitted but bars and restaurants are shut for sit-in service. Schools will remain open but people are being advised to work from home where possible and only undertake necessary travel. All non-essential shops are closed with supermarkets and builders' merchants remaining open. (Photo by Christopher Furlong/Getty Images)
Getty ImagesA recent study that included over 22 million adult patients from South Korea and Japan revealed that an acute Covid-19 infection could be linked to a higher risk of developing autoimmune inflammatory rheumatic diseases up to one year after getting infected.
This includes conditions like rheumatoid arthritis, psoriatic arthritis, Sjögren syndrome, systemic sclerosis, polymyalgia rheumatica, mixed connective tissue disease, dermatomyositis, polymyositis, polyarteritis nodosa, or vasculitis. According to the study's findings, even vaccinated patients who survived a severe Covid-19 infection could be at a higher risk of suffering from one of these conditions.
The researchers based in Seoul, South Korea, analyzed data from two national population-based cohort studies in Japan and Korea to delve into how Covid-19 impacts longterm risk for autoimmune inflammatory rheumatic diseases (AIRD). The data belonged to more than 10 million Koreans and 12 million Japanese adults who were older than 20 years. That included patients who tested positive for Covid-19 from 2020 to 2021.
The team gained access to every study participants' demographic and mortality data from each country's insurance database. They also studied the participants' history of cardiovascular disease, chronic kidney disease, and respiratory diseases.
Among the South Korean participants, 3.9% of them had a history of Covid-19 and close to 1% had been diagnosed with influenza in the past. The percentage of Japanese participants who had Covid-19 was higher at 8.2% and again, close to 1% reported having a case of influenza.
"We found increased risk for incident AIRD up to 12 months after COVID-19 diagnosis compared with influenza-infected and uninfected control patients. Greater severity of acute COVID-19 was associated with higher risk for incident AIRD," the researchers noted.
However, the researchers admitted that the study has several limitations. Their results were from a period of the Covid-19 pandemic before the Omicron variant had emerged. Also, the team highlighted that certain AIRD outcomes were uncommon and some of their estimates were "imprecise."
Three studies that were published in 2023 also found an elevated risk for autoimmune inflammatory rheumatic diseases (AIRD) among people who tested positive for Covid-19 compared to those who did not get a Covid-19 diagnosis. A study published in Clinical Rheumatology with study participants who got Covid-19 in 2020 reported a 42.63% heightened risk for developing an autoimmune disease after catching the SARS-CoV-2 virus.
An autoimmune rheumatic disease affects and disables a target cell and human tissue. The most common one is rheumatoid arthritis in which the immune system attacks healthy cells and causes inflammation, swelling, and debilitating pain in several joints.
Rheumatoid arthritis and systemic lupus erythematosus (SLE) most commonly affect women with a prevalence rate that is greater than 1% of the adult female population in the United States of America. Because these diseases mainly occur in mid to late adulthood, the major comorbidities for rheumatic autoimmune diseases are premature cardiovascular disease and osteoporosis.
The study was recently published in the journal Annals of Internal Medicine.
Therapeutic Activity Of Agonistic Monoclonal Antibodies Against CD40 In A Chronic Autoimmune Inflammatory Process
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Treating Chronic Inflammatory Demyelinating Polyneuropathy
Chronic inflammatory demyelinating polyneuropathy (CIDP) results in disability through immune-mediated nerve injury, which can lead to irreversible deficits after the inflammatory component of CIDP is treated.
The 2021 guideline for CIDP diagnosis and treatment from the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) strongly recommends initial treatment for both typical and variant CIDP forms with intravenous immunoglobulin (IVIG) or corticosteroids, followed by plasma exchange if that is ineffective. Some patients are refractory to initial treatments and may require a different approach.
Overall, relapses requiring additional treatment have been estimated to occur in 20% to 35% of people with CIDP, and CIDP-associated disability may be severe.
"Disability in CIDP is significant both in the short run and long term," said Richard Lewis, MD, of Cedars-Sinai Medical Center in Los Angeles.
"If treated early, long-term axonal damage and permanent disability can be avoided," Lewis stated. "Treatment decisions need to be based on the severity of the disability and how aggressive the disorder is."
Early treatment hinges on early diagnosis, and delayed diagnosis is very common in CIDP, noted Jeffrey Allen, MD, of the University of Minnesota in Minneapolis.
"The time from symptom onset to diagnosis of CIDP is 10 months or more for most patients," Allen said.
"There are many reasons that misdiagnosis and delayed diagnosis occur," he continued. "More common errors include failure to interpret nerve conduction studies correctly, an overreliance on mild or moderately elevated cerebrospinal fluid protein or using a test-of-treatment -- for example, response after starting IVIG -- as a diagnostic test and relying only on subjective perception of benefit."
CIDP variants, especially distal, multifocal, sensory, and motor CIDP, are especially challenging to diagnose accurately, Allen added.
Initial Treatment
Managing CIDP involves both addressing abnormal immune activity and managing residual symptoms. Initial CIDP treatment is guided by evidence-based therapies that escalate depending on the response, Lewis and Allen noted in a 2022 review.
First-line treatments need to be personalized to find the ideal dose for a particular patient and determine whether long-term treatment is needed at all, they stated. Although many immunosuppressive agents may be used in patients who don't respond, all are unproven and the risk, cost, and unknown likelihood of benefit must be balanced, they added.
"There is no reliable disease activity biomarker that can be used to guide treatment -- a reality that makes it very challenging to optimize treatment to individual patient needs," Lewis and Allen pointed out.
The EAN/PNS treatment guideline calls for IVIG or corticosteroids as initial treatment in all CIDP types, with IVIG as the first-line treatment in motor CIDP. The choice of IVIG versus corticosteroid treatment is rooted in patient considerations, the guideline authors noted.
IVIG induction treatment is typically a total dose of 2 g/kg, divided over 2 to 5 days. Two to five repeated doses of 1 g/kg IVIG every 3 weeks may be needed in some patients before improvement or ineffectiveness can be determined.
Observational studies and clinical experience strongly suggest that corticosteroids are effective in CIDP, the guideline authors wrote. The best corticosteroid regimen is not known, and pulsed high-dose corticosteroid treatment with oral dexamethasone or IV methylprednisolone may be considered as an alternative to daily oral prednisone/prednisolone or dexamethasone, they added. Treatment response usually starts after several weeks or months, and a dose reduction of corticosteroids should be attempted regularly to minimize doses and determine whether a patient is in remission.
If IVIG or corticosteroids are ineffective, the EAN/PNS guideline strongly recommends plasma exchange, using peripheral veins if possible. "Plasma exchange requires good vascular access and specialized equipment," the guideline authors noted. "These drawbacks make plasma exchange, despite its effectiveness and relative safety, the third option for chronic treatment after corticosteroids and IVIG."
Maintenance Treatment
Corticosteroids, IVIG, and plasma exchange are also used as maintenance therapies to help prevent relapses.
"Although up to 30% of CIDP patients can go into remission off treatment, only about 10% can remain off treatment for 5 years," Lewis said. "Tapering treatments can be done but must be weighed over risk for relapse."
In 2018, the PATH study showed benefit for subcutaneous immunoglobulin (SCIG) as maintenance treatment, leading to the first FDA approval of SCIG (Hizentra) in CIDP.
In 2024, hyaluronidase-facilitated SCIG (Hyqvia) became another maintenance treatment option. In the phase III ADVANCE-CIDP1 trial, facilitated SCIG led to a CIDP relapse rate of 9.7% versus 31.5% with placebo (difference -21.8%, P=0.0045). Like other immunoglobulin products, facilitated SCIG contains a black box warning for thrombosis. The treatment also is approved for primary immunodeficiency.
Maintenance CIDP treatment may be required with other therapies if IVIG, SCIG, plasma exchange, or corticosteroids are ineffective or require problematically high doses. Immunosuppressants used in the maintenance role include azathioprine and cyclophosphamide, among others.
EAN/PNS guidance about other agents includes a weak recommendation against methotrexate or fingolimod (Gilenya) and a strong recommendation against interferon beta-1a. Guideline authors also cited significant morbidities and mortality risk for hematopoietic stem cell transplantation and concluded it should be considered only as a last-resort option in specialized CIDP centers.
The sparse evidence base for CIDP maintenance therapies has led to an ongoing search for alternative treatments. Efgartigimod combined with hyaluronidase (Vyvgart Hytrulo), a subcutaneous drug approved for myasthenia gravis, inhibits recycling of circulating immunoglobulin G and is one treatment being studied. The investigational agent riliprubart, a complement C1s inhibitor, is another. A new study comparing riliprubart and IVIG as maintenance CIDP therapy will be underway soon.
Disclosures
The 2021 EAN/PNS guideline task force was supported by the European Academy of Neurology, the Peripheral Nerve Society, the GBS/CIDP Foundation International, and the GAIN Charity U.K.
Lewis reported relationships with Argenx, CSL Behring, Sanofi, Grifols, Roche, Alexion, Boehringer Ingelheim, and Alnylam.
Allen reported relationships with Argenx, CSL Behring, Takeda, Grifols, and Alexion.
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The JAK/STAT signaling pathway: from bench to clinic | Signal Transduction and Targeted Therapy
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