What's new in Rheumatology 2022

Author:
Monica Ramirez Curtis, MD, MPH

CRYSTAL DISEASE

Gout flare and risk of subsequent cardiovascular event (August

2022)
Gout is known to be associated with cardiovascular disease;
however, the temporal association of cardiovascular events after an
acute gout flare had not previously been studied. In a case-control
study that included over 62,500 patients with gout in a longitudinal
primary care database, of whom nearly 10,500 experienced a
cardiovascular event (ie, stroke or myocardial infarction), acute gout
flare was associated with increased risk of a cardiovascular event in
the next 0 to 60 days (adjusted odds ratio [aOR] 1.93) and 61 to 120
days (aOR 1.57) [1]. These findings highlight the importance of
managing cardiovascular risk factors among patients with gout.

PEDIATRIC RHEUMATOLOGY

Immunomodulatory therapy for multisystem inflammatory

syndrome in children (April 2022)
The American College of Rheumatology and the United States
National Institutes of Health have published updated guidance on
the management of multisystem inflammatory syndrome in children
(MIS-C) based upon accumulating observational data and clinical
experience [2,3]. Our approach to immunomodulatory therapy in
patients with MIS-C is consistent with these guidelines. In particular,
for most patients who meet diagnostic criteria for MIS-C, we suggest
treatment with both intravenous immune globulin (IVIG) and
glucocorticoids rather than either drug alone.

RHEUMATOID ARTHRITIS
Phase 3 trial of okolizumab for rheumatoid arthritis (September
2022)
Olokizumab is an investigational monoclonal antibody that targets
the interleukin-6 cytokine directly. A recent phase 3 trial compared
olokizumab (dosed every two or four weeks), adalimumab (a tumor
necrosis factor inhibitor), and placebo in 464 patients with
rheumatoid arthritis (RA) receiving treatment with methotrexate [4].
At 12 weeks, the proportion of patients who achieved an American
College of Rheumatology 20 response (≥20 percent fewer tender and
swollen joints and ≥20 percent improvement in three of five other
domains) was greater for olokizumab versus placebo and similar for
olokizumab adalimumab. The incidence of serious adverse events
was similar across the three groups. Larger and longer-term trials are
needed to further evaluate the efficacy and safety of olokizumab in
the treatment of RA.

Add-on low-dose glucocorticoids in older patients with rheumatoid

arthritis (August 2022)
Although short-term use of low-dose glucocorticoids is common in
the management of rheumatoid arthritis (RA), evidence is conflicting
regarding its efficacy and safety when used on a chronic basis. In a
randomized trial of 451 patients with RA aged 65 years and older, the
addition of prednisolone 5 mg daily to disease-modifying therapy
resulted in lower measures of disease activity (0.37 points lower on a
10-point scale) and joint damage progression (1.7 points lower on a
10-point scale) compared with placebo after two years of follow-up
[5]. However, patients in the prednisolone arm experienced more
adverse events (60 versus 49 percent), which consisted mostly of
nonserious infections. Thus, while some patients may experience
modest benefit with add-on low-dose glucocorticoids, the lowest
effective dose should be used to minimize harms, if it is not possible
to discontinue glucocorticoid therapy.
Methotrexate for prevention of rheumatoid arthritis (August 2022)
Various medical therapies have been evaluated for the prevention of
rheumatoid arthritis (RA) among patients considered to be at high
risk for developing clinically active disease. In the TREAT EARLIER trial
that included 236 patients with arthralgias who were suspected of
progressing to RA based on magnetic resonance imaging (MRI)-
detected subclinical joint inflammation, patients who were randomly
assigned to receive a one-year course of oral methotrexate had
similar rates of developing clinical arthritis compared with those who
took placebo (19 versus 18 percent, respectively) [6]. However, there
were greater improvements in self-reported measures of physical
function, pain, and morning stiffness, as well as MRI-detected joint
inflammation, in the methotrexate-treated group, which supports
the role of methotrexate as an effective disease-modifying treatment
among patients in the early phases of the disease.

SPONDYLOARTHRITIS AND PSORIATIC ARTHRITIS

Upadacitinib for nonradiographic axial spondyloarthritis (August

2022)
While janus kinase (JAK) inhibitors such as upadacitinib are effective
in ankylosing spondylitis (AS), their role in nonradiographic axial
spondyloarthritis (nr-axSpA), a potentially earlier form of AS, remains
unclear. In a randomized trial in 313 patients with active nr-axSpA,
upadacitinib resulted in a higher Assessment of SpondyloArthritis
International Society 40 percent (ASAS40) response rate than
placebo at 14 weeks (45 versus 23 percent) [7]. Rates of adverse
events were similar between the two groups. These findings support
the use of upadacitinib for patients with nr-axSpA.
 SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S

SYNDROME

Trial of litifilimab for systemic lupus erythematosus (September

2022)
Blood dendritic cell antigen 2 (BDAC2) is a receptor that is expressed
exclusively on plasmacytoid dendritic cells, which are thought to play
a role in the pathogenesis of systemic lupus erythematosus (SLE). In
a phase 2 trial including 132 patients with SLE, arthritis, and active
skin disease, patients who were randomly assigned to receive
litifilimab (a subcutaneously injected monoclonal antibody that binds
BDAC2) demonstrated a greater reduction from baseline in the
number of swollen and tender joints compared with the placebo
group at 24 weeks (mean difference -3.4) [8]. Serious adverse effects
were reported in 5 versus 11 percent of the litifilimab and placebo
groups, respectively. Additional longer term data are needed to
determine the safety and efficacy of litifilimab for the treatment of
SLE.

Oral tacrolimus versus intravenous cyclophosphamide for lupus

nephritis (August 2022)
Calcineurin inhibitors (CNIs) in combination
with mycophenolate (MMF) have been used for initial therapy for
lupus nephritis (LN) as an alternative to cyclophosphamide, but the
efficacy of CNIs without MMF remains unclear. In a trial that
randomly assigned over 300 patients with LN to oral tacrolimus or
intravenous cyclophosphamide for 24 weeks, the rate of complete
response was higher in the tacrolimus group (50 versus 36 percent)
[9]. Rates of serious treatment-emergent adverse events were lower
in the tacrolimus group; however, patients receiving tacrolimus had
an increase in serum creatinine that was sustained for the duration
of the trial. Although additional longer-term studies are needed to
confirm these findings, we continue to suggest glucocorticoids in
combination with MMF or cyclophosphamide alone for initial
therapy of focal or diffuse LN.

VASCULITIS

Rituximab for adults >75 years old with ANCA-associated vasculitis

(August 2022)
Rituximab has been shown to be efficacious in patients with
granulomatosis with polyangiitis (GPA) or microscopic polyangiitis
(MPA), but randomized trials included few patients who were 75
years or older. An observational study of 93 adults aged >75 years
with GPA or MPA found that rituximab for induction and/or
maintenance therapy was associated with remission in most patients
and low rates of relapse [10]. However, rates of serious infection
were high (46.6 per 100 patient-years) among patients receiving
rituximab for induction therapy. These findings support the use of
rituximab in patients 75 years old but highlight the risk of serious
infections in this patient population.

VEXAS syndrome in patients with vasculitis (June 2022)

Since the adult-onset inflammatory disorder known as VEXAS
(vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic)
syndrome was first described, it has been associated with several
forms of vasculitis including giant cell arteritis, polyarteritis nodosa,
and relapsing polychondritis. A case series from a single-center
cohort of patients with vasculitis has reported the first case of a
patient with VEXAS syndrome associated with antineutrophil
cytoplasmic autoantibody-associated vasculitis [11]. VEXAS
syndrome should be considered in adult males with unexplained
cytopenias and/or refractory or persistent symptoms of vasculitis.
 OTHER RHEUMATOLOGY

Perioperative management of biologic disease-modifying

antirheumatic drugs (September 2022)
There is limited evidence to inform the optimal timing of use for
biologic disease-modifying antirheumatic drugs (DMARDs) in the
perioperative period among patients with systemic rheumatic
diseases. In a meta-analysis of cohort studies including over 7300
patients on biologic DMARDs for systemic rheumatic diseases who
were undergoing surgery, patients who continued biologics did not
appear to be at an increased risk for surgical site infection or delayed
wound healing [12]. Stopping biologics prior to surgery, however,
was associated with higher rates of disease flares (26 versus 7
percent). These findings are limited by the retrospective and
heterogenous nature of the evidence. Our general approach to
patients on biologic DMARDs undergoing elective surgery is to
withhold the medication at the end of the dosing cycle if disease
activity permits.

Steroid injection for Achilles tendinopathy (August 2022)

Debate continues about the appropriate role for glucocorticoid
injection in the treatment of chronic tendinopathy. In a blinded,
randomized trial of 100 patients with Achilles tendinopathy causing
symptoms for a minimum of three months and who received
exercise therapy, those assigned to glucocorticoid injection
experienced greater functional and symptomatic improvement at
three and six months compared with patients given placebo
injections [13]. However, no significant difference in functional
outcomes or tendon thickness was noted at 12 or 24 months. These
findings, which are consistent with other studies, support our limited
use of glucocorticoid injections as adjunct therapy early in the
treatment of chronic tendinopathy. Such injections may be most
helpful for patients with persistent pain who are unable to
participate in physical therapy.

Ultrasound- versus landmark-guided technique for joint aspirations

(July 2022)
Although some joint aspirations may be performed using anatomic
landmarks, the use of ultrasound guidance has been shown to
improve accuracy of needle placement in previous studies. In a
randomized trial including 44 patients presenting to an emergency
department with a suspected moderate-size joint effusion involving
the elbow, wrist, or ankle, a greater number of successful aspirations
were performed with ultrasound guidance compared with landmark-
guided aspirations (94 versus 60 percent) [14]. Notably, of the 14
landmark-guided aspirations for which arthrocentesis was initially
unsuccessful, 8 of the patients had no effusion when subsequently
evaluated with ultrasonography. This small study supports the use of
ultrasound guidance to improve the success rates of arthrocentesis
of medium-sized joints.

Apixaban versus warfarin for thrombotic antiphospholipid

syndrome (May 2022)
Warfarin is recommended for patients with thrombotic
antiphospholipid syndrome (APS) based on data showing superiority
of warfarin over the direct oral anticoagulant (DOAC) rivaroxaban. In
a new trial that randomly assigned 48 patients with thrombotic APS
to receive warfarin or the DOAC apixaban, there were no strokes in
the 25 patients assigned to warfarin; 6 of 23 patients assigned to
apixaban had a stroke [15]. Although the trial had important
limitations including early termination, small sample size, and an
initially low dose of apixaban, these findings add to the evidence that
warfarin is more effective than DOACs for recurrent thrombosis
prevention in patients with thrombotic APS.

Tixagevimab-cilgavimab for pre-exposure prophylaxis against

COVID-19 (May 2022)
The monoclonal antibody combination tixagevimab-cilgavimab is a
potential option for pre-exposure prophylaxis against COVID-19 for
certain immunocompromised individuals (table 1) who may not
benefit maximally from vaccination and for those who have a
contraindication to vaccination. In a placebo-controlled, randomized
trial of over 5000 unvaccinated adults, a single dose of tixagevimab-
cilgavimab reduced the risk of symptomatic infection by 77 percent
[16]. Overall, serious adverse event rates were similar to those with
placebo. However, among individuals with cardiovascular risk, severe
cardiac events were rare but more frequent with tixagevimab-
cilgavimab. For those who meet eligibility criteria, we individualize
the decision to use tixagevimab-cilgavimab, taking into account risk
of exposure and severe disease, underlying comorbidities, and
patient preference.

COVID-19 vaccine safety in people with rheumatologic diseases

(April 2022)
There are limited data regarding the risk of flare of existing
rheumatic disease following COVID-19 vaccination. In a large cohort
including over 4600 patients with inflammatory systemic rheumatic
diseases who received one or more doses of any COVID-19 vaccine,
approximately 4 percent of patients experienced a disease flare at a
mean of six days following vaccination [17]. The majority of flares
were mild to moderate in severity, with approximately one-third of
the flares resulting in medication changes. These findings support
the routine use of COVID-19 vaccination in patients with systemic
rheumatic diseases.
 Updated American College of Rheumatology COVID-19 vaccine
clinical guidance (March 2022)
The American College of Rheumatology has updated their clinical
guidance for the management of patients with systemic rheumatic
disease during the pandemic, including the appropriateness of
COVID-19 vaccine boosters and the use of pre- and postexposure
prophylactic therapies [18]. This guidance is generally consistent with
the Centers for Disease Control and Prevention recommendations
regarding immunocompromised patients.

REFERENCES

1. Cipolletta E, Tata LJ, Nakafero G, et al. Association Between Gout

Flare and Subsequent Cardiovascular Events Among Patients With
Gout. JAMA 2022; 328:440.
2. Henderson LA, Canna SW, Friedman KG, et al. American College of
Rheumatology Clinical Guidance for Multisystem Inflammatory
Syndrome in Children Associated With SARS-CoV-2 and
Hyperinflammation in Pediatric COVID-19: Version 3. Arthritis
Rheumatol 2022; 74:e1.
3. Therapeutic Management of Hospitalized Pediatric Patients With Mu
ltisystem Inflammatory Syndrome in Children (MIS-C) (With Discussio
n on Multisystem Inflammatory Syndrome in Adults [MIS-A]) https://
www.covid19treatmentguidelines.nih.gov/management/clinical-man
agement/hospitalized-pediatric-patients--therapeutic-management-
of-mis-c/ (Accessed on February 25, 2022).
4. Smolen JS, Feist E, Fatenejad S, et al. Olokizumab versus Placebo or
Adalimumab in Rheumatoid Arthritis. N Engl J Med 2022; 387:715.
5. Boers M, Hartman L, Opris-Belinski D, et al. Low dose, add-on
prednisolone in patients with rheumatoid arthritis aged 65+: the
pragmatic randomised, double-blind placebo-controlled GLORIA trial.
Ann Rheum Dis 2022; 81:925.
6. Krijbolder DI, Verstappen M, van Dijk BT, et al. Intervention with
methotrexate in patients with arthralgia at risk of rheumatoid
 arthritis to reduce the development of persistent arthritis and its
disease burden (TREAT EARLIER): a randomised, double-blind,
placebo-controlled, proof-of-concept trial. Lancet 2022; 400:283.
7. Deodhar A, Van den Bosch F, Poddubnyy D, et al. Upadacitinib for
the treatment of active non-radiographic axial spondyloarthritis
(SELECT-AXIS 2): a randomised, double-blind, placebo-controlled,
phase 3 trial. Lancet 2022; 400:369.
8. Furie RA, van Vollenhoven RF, Kalunian K, et al. Trial of Anti-BDCA2
Antibody Litifilimab for Systemic Lupus Erythematosus. N Engl J Med
2022; 387:894.
9. Zheng Z, Zhang H, Peng X, et al. Effect of Tacrolimus vs Intravenous
Cyclophosphamide on Complete or Partial Response in Patients With
Lupus Nephritis: A Randomized Clinical Trial. JAMA Netw Open 2022;
5:e224492.
10. Thietart S, Karras A, Augusto JF, et al. Evaluation of Rituximab
for Induction and Maintenance Therapy in Patients 75 Years and
Older With Antineutrophil Cytoplasmic Antibody-Associated
Vasculitis. JAMA Netw Open 2022; 5:e2220925.
11. Muratore F, Marvisi C, Castrignanò P, et al. VEXAS Syndrome: A
Case Series From a Single-Center Cohort of Italian Patients With
Vasculitis. Arthritis Rheumatol 2022; 74:665.
12. van Duren BH, Wignall A, Goodman S, et al. The Effect of
Perioperative Biologic Disease-Modifying Anti-Rheumatic Drugs on
the Risk of Postoperative Complications: Surgical Site Infection,
Delayed Wound Healing, and Disease Flares Following Orthopaedic
Surgical Procedures. J Bone Joint Surg Am 2022.
13. Johannsen F, Olesen JL, Øhlenschläger TF, et al. Effect of
Ultrasonography-Guided Corticosteroid Injection vs Placebo Added
to Exercise Therapy for Achilles Tendinopathy: A Randomized Clinical
Trial. JAMA Netw Open 2022; 5:e2219661.
14. Gibbons RC, Zanaboni A, Genninger J, Costantino TG.
Ultrasound-versus landmark-guided medium-sized joint
arthrocentesis: A randomized clinical trial. Acad Emerg Med 2022;
29:159.
15. Woller SC, Stevens SM, Kaplan D, et al. Apixaban compared
with warfarin to prevent thrombosis in thrombotic antiphospholipid
syndrome: a randomized trial. Blood Adv 2022; 6:1661.
16. Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular
AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19. N
Engl J Med 2022; 386:2188.
17. Machado PM, Lawson-Tovey S, Strangfeld A, et al. Safety of
vaccination against SARS-CoV-2 in people with rheumatic and
musculoskeletal diseases: results from the EULAR Coronavirus
Vaccine (COVAX) physician-reported registry. Ann Rheum Dis 2022;
81:695.
18. https://www.rheumatology.org/Portals/0/Files/COVID-19-Vacci
ne-Clinical-Guidance-Rheumatic-Diseases-Summary.pdf (Accessed on
February 07, 2022).