Long COVID and rheumatology: Clinical, diagnostic, and therapeutic implications.

As of this writing, it is estimated that there have been nearly 600 million cases of coronavirus disease 2019 (COVID-19) around the world with over six million deaths. While shocking, these figures do not fully illustrate the morbidity associated with this disease. It is also estimated that between 10% and 30% of those who survive COVID-19 develop persistent symptoms after the acute infection has passed. These individuals, who most often experienced initial infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) considered mild to moderate in severity, often display a broad array of symptoms. Collectively, this disorder or syndrome is now referred to as Long COVID (among other designations), and it represents a national/international health crisis. The most frequently reported symptoms associated with Long COVID include chronic fatigue with post exertional features, neurocognitive dysfunction, breathlessness, and somatic pain. Long COVID can range in severity from mild to severely debilitating, with resultant loss of quality of life and productivity. For now, there are many unanswered questions surrounding Long COVID: how can it be best defined, what is needed for accurate diagnosis, what is causing it, and how should it be best managed. How rheumatologists will engage in the Long COVID pandemic is another question; at the minimum, we will be called upon to evaluate and manage our own patients with immune-mediated inflammatory diseases who have developed it. This review focuses on addressing the disease essentials, providing both declarative and procedural knowledge to prepare rheumatologists for how to address Long COVID: understanding its origins, its current case definitions, epidemiology, pathobiology and clinical manifestations. Finally, it will provide an outline on how to clinically approach patients with possible Long COVID and initiate treatment and/or guide them on how to best manage it.

Breakthrough SARS-CoV-2 Infections in Patients With Immune-Mediated Disease Undergoing B Cell-Depleting Therapy: A Retrospective Cohort Analysis.

OBJECTIVE: Patients with immune-mediated inflammatory diseases (IMIDs) receiving B cell-depleting therapy (BCDT) are among the most vulnerable to severe COVID-19, as well as the most likely to suboptimally respond to SARS-CoV-2 vaccines. However, little is known about the frequency or severity of breakthrough infection in this population. We retrospectively analyzed a large group of vaccinated IMID patients undergoing BCDT in order to identify breakthrough COVID-19 infections and assess their outcomes. METHODS: In this retrospective cohort study, the pharmacy records and COVID-19 registry at the Cleveland Clinic were searched using specific International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes to identify IMIDs patients who 1) received treatment with BCDT, 2) were vaccinated against SARS-CoV-2, and 3) experienced breakthrough infections. Each electronic medical record was reviewed to extract clinical data and outcomes. Univariate and multivariable logistic/proportional odds regression models were used to examine the risk factors for severe outcomes. RESULTS: Of 1,696 IMID patients receiving BCDT, 74 developed breakthrough COVID-19 prior to December 16, 2021. Outcomes were severe, with 29 patients hospitalized (39.2%), 11 patients requiring critical care (14.9%), and 6 deaths (8.1%). Outpatient anti-SARS-CoV-2 monoclonal antibodies were used to treat 21 patients, with 1 hospitalization and no deaths. A comparator analysis examining 1,437 unvaccinated IMID patients receiving BCDT over the same time period identified 57 COVID-19 cases (4.0%), with 28 requiring hospitalization (49.1%), including 7 deaths (12.3%). CONCLUSION: IMID patients receiving BCDT regardless of vaccine status appear to be vulnerable to infection with SARS-CoV-2, and use of BCDT is frequently associated with severe outcomes. Outpatient use of anti-SARS-CoV-2 monoclonal antibody therapy appears to be associated with enhanced clinical outcomes.

Safety of recombinant zoster vaccine: a retrospective study of 622 rheumatology patients.

OBJECTIVES: To provide insight into the safety of recombinant zoster vaccine (RZV) in patients with immune-mediated inflammatory diseases (IMID). METHODS: Patients who received RZV in a single-centre rheumatology department were retrospectively included. An IMID flare was defined as (i) a documentation of flare in the office notes or patient portal communication or (ii) new prednisone prescription, in the 12 weeks after each dose. RESULTS: Six-hundred and twenty-two patients were included (67% female, median age 67 years), 8.5% of them experienced adverse events (AEs) and herpes zoster (HZ) incidence was 0.6% after median follow-up of 36 weeks. Of 359 IMID patients: 88 had RA (25%), 50 vasculitis (14%) and 29 PMR (8%). At vaccination, 35% were on glucocorticoids (GC). Fifty-nine patients (16%) experienced a flare, 18 flares occurred in temporal relation to a treatment change (31%). RA patients had the highest flare rate (n = 21, 24%), 25% of patients who flared required adjustment of immunosuppression. In a multivariate analysis, use of GC at time of vaccination was associated with flare after vaccination [odds ratio (OR) 2.31 (1.3-4.1), P =0.004]. A time-to-flare survival analysis (Cox-model) showed that GC was a significant predictor of IMID flare after first RZV dose [hazard ratio (HR) 2.4 (1.3-4.5), P =0.0039] and that a flare after the first dose was associated with flaring after the second RZV dose [HR 3.9 (1.7-9), P =0.0015]. CONCLUSION: RZV administration in patients with IMIDs was generally well-tolerated, though mild flares were not uncommon in the first 12 weeks after vaccination. These data may provide useful information for patient education when considering RZV administration.

Infections in the Era of Targeted Therapies: Mapping the Road Ahead.

Immunosuppressive treatment strategies for autoimmune diseases have changed drastically with the development of targeted therapies. While targeted therapies have changed the way we manage immune mediated diseases, their use has been attended by a variety of infectious complications-some expected, others unexpected. This perspective examines lessons learned from the use of different targeted therapies over the past several decades, and reviews existing strategies to minimize infectious risk. Several of these infectious complications were predictable in the light of preclinical models and early clinical trials (i.e., tuberculosis and TNF inhibitors; meningococcus; and eculizumab). While these scenarios can potentially help us in terms of enhancing our predictive powers (higher vigilance, earlier detection, and risk mitigation), targeted therapies have also revealed unpredictable toxicities (i.e., natalizumab and progressive multifocal leukoencephalopathy). Severe infectious complications, even if rare, can derail a promising therapeutic and highlight the need for increased awareness and meticulous adjudication. Tools are available to help mitigate infectious risks. The first step is to ensure that infection safety is adequately studied at every level of drug development prior to regulatory approval, with adequate post-marketing surveillance including registries that collect real-world adverse events in a collaborative effort. The second step is to identify high risk patients (using risk calculators such as the RABBIT risk score; big data analyses; artificial intelligence). Finally, the most underutilized interventions to prevent severe infections in patients receiving targeted therapies across the spectrum of immune mediated inflammatory diseases are vaccinations.

Polymyalgia rheumatica-like syndrome from checkpoint inhibitor therapy: case series and systematic review of the literature.

Objective: To assess whether the polymyalgia rheumatica (PMR)-like syndrome reported as an immune related adverse event (irAE) from checkpoint inhibitor therapy is consistent with the 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) provisional criteria for PMR. Methods: The cases were derived from two sources. Group 1 represents reported cases from three contributing centres. Group 2 was derived from a systematic review of the literature searching for all cases reported as PMR or PMR-like illness associated with checkpoint inhibitor therapy. Cases were assessed for the quality of reporting and then analysed to determine whether they fulfilled the 2012 EULAR/ACR provisional criteria for PMR. Results: A total of 49 patients were included for analysis. Among the entire group, 37 (75%) were designated 'complete' indicating that they had sufficient data to reliably apply the 2012 EULAR/ACR criteria. 28 (75%) cases fulfilled complete criteria for PMR. A number of cases also demonstrated some clinical features unusual for idiopathic PMR. Conclusion: This study suggests a high proportion of reported cases of checkpoint inhibitor-related PMR fulfil preliminary criteria for PMR, yet in one quarter clinical details were incomplete making verification problematic. Furthermore, in the absence of a gold standard for the diagnosis of PMR, the relationship of checkpoint inhibitor-related PMR to the idiopathic form remains unclear.

Myalgia and Arthralgia Immune-related Adverse Events (irAEs) in Patients With Genitourinary Malignancies Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Myalgia and arthralgia immune-related adverse events (irAEs) in patients treated with checkpoint inhibitors (CPIs) present a clinical challenge. We describe the clinical characteristics and treatment of myalgia and arthralgia irAEs in CPI-treated patients with genitourinary (GU) malignancies. PATIENTS AND METHODS: Patients with GU malignancies who were treated with CPIs and developed myalgia and arthralgia irAEs that resulted in interruption or discontinuation of CPI therapy were reviewed. Patient-, disease-, and irAE-related data were collected and analyzed. RESULTS: Twenty-one patients were identified. Eighteen (86%) had renal cell carcinoma; 3 (14%) had urothelial carcinoma. The majority (71%) were male; the median age at diagnosis was 56 years (range, 36-78 years). CPI therapy included anti-programmed death-ligand 1 (29%), anti-programmed cell death protein 1 (48%), and combined programmed cell death protein 1/cytotoxic T-lymphocyte-associated protein 4 antibodies (24%). The median time from CPI initiation to myalgia and arthralgia irAE was 5.1 months (range, 0.23-50.5 months). All patients were treated with prednisone with a median initial dose of 40 mg/d (range, 10-90 mg/d) for a median duration of 64 weeks (range, 3-242 weeks). Treatment with methotrexate (14%), infliximab (14%), tocilizumab (10%), gabapentin (10%), and etanercept (5%) was also required in some patients. Six (29%) patients restarted CPI therapy following symptom improvement, 3 (15%) switched to a subsequent therapy, and 12 (55%) patients had an ongoing sustained response to therapy (median, 14.5 months; range, 3-55 months) despite no subsequent anti-cancer therapy. CONCLUSION: Myalgia and arthralgia irAEs in CPI-treated patients with GU malignancies vary in timing of presentation, severity, and treatment. Multidisciplinary teams that include a rheumatologist are critical for optimal management. Durable response to CPIs can be maintained even after therapy discontinuation.

Rheumatoid Arthritis: Pathophysiology and Safe Administration of Biologics.

Approximately 1 in 5 people in the United States suffers from autoimmune diseases. To explain the pathophysiology of autoimmune disease, a basic understanding of the normal and dysfunctional immune system is necessary. Rheumatoid arthritis is used as a model to explain the basics of autoimmune disease. The infusion nurse plays a key role in patient education and the safe administration of biologics.

Barriers to Immunizations and Strategies to Enhance Immunization Rates in Adults with Autoimmune Inflammatory Diseases.

For as long as there have been immunizations, there have been barriers to them. Immunization rates in the United States are below target. Rheumatologists and rheumatology practitioners need to understand the issues of immunizations in patients with autoimmune inflammatory disease to identify and overcome barriers to immunization. Several strategies for overcoming these barriers are discussed.

Heart transplantation in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

BACKGROUND: Heart involvement is the leading cause of death of patients with eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) and is more frequent in anti-neutrophil cytoplasm antibody (ANCA)-negative patients. Post-transplant outcome has only been reported once. METHODS: We conducted a retrospective international multicenter study. Patients satisfying the criteria of the American College of Rheumatology and/or revised Chapel Hill Consensus Conference Nomenclature were identified by collaborating vasculitis and transplant specialists, and the help of the Churg-Strauss Syndrome Association. RESULTS: Nine ANCA(-) patients who received transplants between October 1987 and December 2009 were identified. The vasculitis and cardiomyopathy diagnoses were concomitant for 5 patients and separated by 12 to 288 months for the remaining 4 patients. Despite ongoing immunosuppression, histologic examination of 7 (78%) patients' explanted hearts showed histologic patterns suggestive of active vasculitis. The overall 5-year survival rate was low (57%), but rose to 80% when considering only the 6 patients transplanted during the last decade. After survival lasting 3 to 60 months, 4 (44%) patients died sudden deaths. CONCLUSIONS: The search for EGPA-related cardiomyopathy is mandatory early in the course of this type of vasculitis. Indeed, prompt treatment with corticosteroids and cyclophosphamide may achieve restore cardiac function. Most patients in this series were undertreated. For patients with refractory EGPA, heart transplantation should be performed, which carries a fair prognosis. No optimal immunosuppressive strategy has yet been identified.

The frequency of low muscle mass and its overlap with low bone mineral density and lipodystrophy in individuals with HIV--a pilot study using DXA total body composition analysis.

As a result of the advances in antiretroviral therapy, the life span of human immunodeficiency virus (HIV)-infected patients has increased dramatically. Attendant to these effects are signs of premature aging with notable changes in the musculoskeletal system. Although changes in bone and fat distribution have been studied extensively, far less is known about changes in muscle. This study examined the extent of low muscle mass (LMM) and its relationship with low bone mineral density (BMD) and lipodystrophy (LD) in HIV-positive males. As such, HIV-positive males on therapy or treatment naive underwent dual-energy X-ray absorptiometry total body composition measurements. Appendicular lean mass/(height)2 and lowest 20% of residuals from regression analysis were used to define LMM. BMD criteria defined osteopenia/osteoporosis, and the percent central fat/percent lower extremity ratio defined LD. Several potential risk factors were assessed through chart review. Sixty-six males (57 with treatment and 9 treatment naive) volunteered. Treated individuals were older than naive (44 vs 34 yr) and had HIV longer (108 vs 14 mo). When definitions for sarcopenia (SP) in elderly individuals were applied, the prevalence of LMM was 21.9% and 18.8% depending on the definition used. Low BMD was present in 68.2% of participants. LD with a cutoff of 1.5 and 1.961 was present in 54.7% and 42.2% of participants, respectively. LMM and LD were negatively associated. In conclusion, this study shows that LMM is common in males with HIV and that SP affecting muscle function could be present in a substantial number of individuals. Future research needs to examine what impact decreased muscle mass and function has on morbidity, physical function, and quality of life in individuals with HIV.

Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells.

BACKGROUND: Failure to normalize CD4(+) T-cell numbers despite effective antiretroviral therapy is an important problem in human immunodeficiency virus (HIV) infection. METHODS: To evaluate potential determinants of immune failure in this setting, we performed a comprehensive immunophenotypic characterization of patients with immune failure despite HIV suppression, persons who experienced CD4(+) T-cell restoration with therapy, and healthy controls. RESULTS: Profound depletion of all CD4(+) T-cell maturation subsets and depletion of naive CD8(+) T cells was found in immune failure, implying failure of T-cell production/expansion. In immune failure, both CD4(+) and CD8(+) cells were activated but only memory CD4(+) cells were cycling at increased frequency. This may be the consequence of inflammation induced by in vivo exposure to microbial products, as soluble levels of the endotoxin receptor CD14(+) and interleukin 6 were elevated in immune failure. In multivariate analyses, naive T-cell depletion, phenotypic activation (CD38(+) and HLA-DR expression), cycling of memory CD4(+) T cells, and levels of soluble CD14 (sCD14) distinguished immune failure from immune success, even when adjusted for CD4(+) T-cell nadir, age at treatment initiation, and other clinical indices. CONCLUSIONS: Immune activation that appears related to exposure to microbial elements distinguishes immune failure from immune success in treated HIV infection.

Rheumatic complications of human immunodeficiency virus infection in the era of highly active antiretroviral therapy: emergence of a new syndrome of immune reconstitution and changing patterns of disease.

OBJECTIVE: To describe the impact of the introduction of highly active antiretroviral therapy (HAART) on the nature and frequency of rheumatic complications in human immunodeficiency virus (HIV)-infected patients. METHODS: Case report and systematic review of a newly described syndrome of rheumatic immune reconstitution syndrome and prospective longitudinal cohort study analyzing the frequency and nature of rheumatic complications in the setting of HIV infection from 1989 through 2000. RESULTS: A newly described syndrome of either the de novo appearance or the exacerbation of clinically occult autoimmunity following immune reconstitution from HAART is described. Including the present case report, 32 cases have been individually described with sarcoidosis and autoimmune thyroid disease being most common with arthritis and various forms of connective tissue disease making up the rest. The mean onset to their appearance following HAART was nearly 9 months and most resolved with little or no therapy. In addition, a longitudinal analysis of 395 HIV-infected patients from 1989 to 2000 designed to detect the appearance of rheumatic complications has revealed a dramatic decline in certain problems such as reactive arthritis, psoriatic arthritis, and various forms of connective tissue disease. New rheumatic complications possibly due to the effects of longer survival and metabolic derangements associated with this form of therapy are now being described and may become more formidable problems in this population in the future. CONCLUSIONS: HAART has had a profound beneficial effect on survival in HIV-infected patients but has also contributed to both an altered frequency and a different nature of rheumatic complications now being observed in this population. Rheumatologists need to be aware of these changes to provide optimal diagnosis and treatment for this group.

Cryoglobulinemic vasculitis and lymphocytic interstitial pneumonitis in a person with HIV infection.

A wide variety of rheumatologic complications have been reported in the setting of HIV-1 infection. We present the case of an HIV-1-infected patient with small-vessel vasculitis and inflammatory lung disease. This case illustrates the complexity of the differential diagnosis of inflammatory and autoimmune disease states in HIV-1-infected patients.