Objective
To evaluate disease flare and postvaccination reactions (reactogenicity) in patients with rheumatic and musculoskeletal diseases (RMDs) following 2‐dose SARS–CoV‐2 messenger RNA (mRNA) ...vaccination.
Methods
RMD patients (n = 1,377) who received 2‐dose SARS–CoV‐2 mRNA vaccination between December 16, 2020 and April 15, 2021 completed questionnaires detailing local and systemic reactions experienced within 7 days of each vaccine dose (dose 1 and dose 2), and 1 month after dose 2, detailing any flares of RMD. Associations between demographic/clinical characteristics and flares requiring treatment were evaluated using modified Poisson regression.
Results
Among the patients, 11% reported flares requiring treatment; there were no reports of severe flares. Flares were associated with prior SARS–CoV‐2 infection (incidence rate ratio IRR 2.09, P = 0.02), flares in the 6 months preceding vaccination (IRR 2.36, P < 0.001), and the use of combination immunomodulatory therapy (IRR 1.95, P < 0.001). The most frequently reported local and systemic reactions included injection site pain (87% after dose 1, 86% after dose 2) and fatigue (60% after dose 1, 80% after dose 2). Reactogenicity increased after dose 2, particularly for systemic reactions. No allergic reactions or SARS–CoV‐2 diagnoses were reported.
Conclusion
Flares of underlying RMD following SARS–CoV‐2 vaccination were uncommon. There were no reports of severe flares. Local and systemic reactions typically did not interfere with daily activity. These early safety data can help address vaccine hesitancy in RMD patients.
Objective
To develop an evidence‐based guideline on contraception, assisted reproductive technologies (ART), fertility preservation with gonadotoxic therapy, use of menopausal hormone replacement ...therapy (HRT), pregnancy assessment and management, and medication use in patients with rheumatic and musculoskeletal disease (RMD).
Methods
We conducted a systematic review of evidence relating to contraception, ART, fertility preservation, HRT, pregnancy and lactation, and medication use in RMD populations, using Grading of Recommendations Assessment, Development and Evaluation methodology to rate the quality of evidence and a group consensus process to determine final recommendations and grade their strength (conditional or strong). Good practice statements were agreed upon when indirect evidence was sufficiently compelling that a formal vote was unnecessary.
Results
This American College of Rheumatology guideline provides 12 ungraded good practice statements and 131 graded recommendations for reproductive health care in RMD patients. These recommendations are intended to guide care for all patients with RMD, except where indicated as being specific for patients with systemic lupus erythematosus, those positive for antiphospholipid antibody, and/or those positive for anti‐Ro/SSA and/or anti‐La/SSB antibodies. Recommendations and good practice statements support several guiding principles: use of safe and effective contraception to prevent unplanned pregnancy, pre‐pregnancy counseling to encourage conception during periods of disease quiescence and while receiving pregnancy‐compatible medications, and ongoing physician‐patient discussion with obstetrics/gynecology collaboration for all reproductive health issues, given the overall low level of available evidence that relates specifically to RMD.
Conclusion
This guideline provides evidence‐based recommendations developed and reviewed by panels of experts and RMD patients. Many recommendations are conditional, reflecting a lack of data or low‐level data. We intend that this guideline be used to inform a shared decision‐making process between patients and their physicians on issues related to reproductive health that incorporates patients’ values, preferences, and comorbidities.
Objective
To determine the safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with statin‐associated anti–3‐hydroxy‐3‐methlyglutaryl coenzyme A reductase ...(anti‐HMGCR)–positive immune‐mediated necrotizing myopathy (IMNM).
Methods
Muscle strength was assessed in anti‐HMGCR–positive patients at each visit before and after initiation of PCSK9 inhibitors. The trends in creatine kinase (CK) levels and serum anti‐HMGCR antibody titers were monitored over time.
Results
Among 122 anti‐HMGCR–positive patients, we identified 8 patients who were receiving PCSK9 inhibitors for hyperlipidemia. Patients were followed up for an average of 1.5 years (range 3–37 months), and none exhibited reduction in muscle strength. The mean ± SD CK level prior to the initiation of PCSK9 inhibitors was 956 ± 1,137 IU/liter, which was reduced to 419 ± 393 IU/liter at their last visit. Anti‐HMGCR antibody titers followed a similar trend. Notably, in 2 patients, the initiation of the lipid‐lowering medication was followed by unanticipated spontaneous clinical improvement and reduction in immunosuppression.
Conclusion
PCSK9 inhibitors are safe for long‐term use as a cholesterol‐lowering agent in patients with statin‐associated IMNM.
Objective
This open‐label 12‐week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in treatment‐refractory active dermatomyositis (DM).
Methods
Tofacitinib in ...extended‐release doses of 11 mg was administered daily to 10 subjects with DM. Prior to treatment, a complete washout of all steroid‐sparing agents was performed. The primary outcome measure was assessment of disease activity improvement based on the International Myositis Assessment and Clinical Studies group definition of improvement. Response rate was measured as the total improvement score according to the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. Secondary outcome measures included Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis, and safety.
Results
At 12 weeks, the primary outcome was met in all 10 subjects. Five (50%) of 10 subjects experienced moderate improvement in disease activity, and the other 50% experienced minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome of the mean change in the CDASI activity score over 12 weeks was statistically significant (mean ± SD 28 ± 15.4 at baseline versus 9.5 ± 8.5 at 12 weeks) (P = 0.0005). Serum chemokine levels of CXCL9/CXCL10 showed a statistically significant change from baseline. A marked decrease in STAT1 signaling in association with suppression of interferon target gene expression was demonstrated in 3 of 9 skin biopsy samples from subjects with dermatomyositis. The mean ± SD level of creatine kinase in the 10 subjects at baseline was 82 ± 34.8 IU/liter, highlighting that disease activity was predominantly located in the skin.
Conclusion
This is the first prospective, open‐label clinical trial of tofacitinib in DM that demonstrates strong clinical efficacy of a pan‐JAK inhibitor, as measured by validated myositis response criteria. Future randomized controlled trials using JAK inhibitors should be considered for treating DM.
Objective
Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with ...autoantibodies recognizing the nuclear matrix protein NXP‐2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti–NXP‐2 autoantibodies.
Methods
There were 235 DM patients who underwent testing for anti–NXP‐2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti–NXP‐2‐positive subjects was compared with the number expected in the general population.
Results
Of the DM patients, 56 (23.8%) were anti–NXP‐2‐positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti–NXP‐2. In contrast, anti–NXP‐2‐positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti–NXP‐2‐positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti–NXP‐2‐negative patients. Five anti–NXP‐2‐positive subjects (9%) had cancer‐associated myositis, representing a 3.68‐fold increased risk (95% confidence interval 1.2–8.6) compared to the expected prevalence in the general population.
Conclusion
In DM, anti–NXP‐2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti–NXP‐2‐positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening.
Objective
Autoantibodies against melanoma differentiation–associated protein 5 (MDA‐5) have been described in several Asian dermatomyositis (DM) cohorts, often associated with amyopathic DM and ...rapidly progressive interstitial lung disease (ILD). A recent study of a DM cohort seen at a US dermatology clinic reports that MDA‐5 autoantibodies are associated with a unique cutaneous phenotype. Given the widening spectrum of clinical findings, we evaluated the clinical features of anti–MDA‐5–positive patients seen at a US myositis referral center.
Methods
One hundred sixty DM patients were screened for MDA‐5 autoantibodies by immunoprecipitation and antibody titers were analyzed in longitudinal serum samples. Anti–MDA‐5–positive patients were evaluated for the presence of additional myositis autoantibodies. Patient clinical characteristics were compared by retrospective chart review.
Results
MDA‐5 was targeted in 11 (6.9%) of 160 patients with DM. Of these, 9 presented with a symmetric polyarthropathy, 6 demonstrated overt clinical myopathy, and 8 had ILD. Eight anti–MDA‐5–positive patients exhibited the clinical attributes of the antisynthetase syndrome in the absence of Jo‐1 or other antisynthetase autoantibodies. MDA‐5 autoantibody titers did not correlate with clinical course.
Conclusion
MDA‐5 autoantibodies are found in DM patients presenting with a symmetric polyarthritis, clinically similar to rheumatoid arthritis. These patients often have features of the antisynthetase syndrome, but in the absence of antisynthetase autoantibodies. Most anti–MDA‐5–positive patients had overt clinical myopathy and ILD. The latter, while occasionally severe, typically resolved with immunosuppressive therapy. In this cohort, the MDA‐5 phenotype is frequently a clinical mimic of the antisynthetase syndrome and is not associated with rapidly progressive ILD.
•Dermatomyositis-specific autoantibodies define unique clinical phenotypes.•Standardized autoantibody detection methods are needed.•Patients with antisynthetase autoantibodies do not have ...dermatomyositis.•A new dermatomyositis classification scheme was proposed.
Objective
To describe the disease specificity, clinical phenotype, and risk of cancer in dermatomyositis (DM) patients with autoantibodies against cell division cycle and apoptosis regulator protein ...1 (anti‐CCAR1).
Methods
The frequency of anti‐CCAR1 autoantibodies was measured by enzyme‐linked immunosorbent assay in the serum of DM patients from 2 independent cohorts (Johns Hopkins and Stanford), with patients with several other rheumatic diseases and healthy controls used as comparators. Clinical features and the risk of cancer incidence relative to that in the general population were determined in anti‐CCAR1–positive DM patients.
Results
Anti‐CCAR1 antibodies were significantly associated with anti–transcriptional intermediary factor 1γ (anti‐TIF1γ) antibodies present in the serum of patients with DM: 80 (32%) of 252 anti‐TIF1γ–positive DM patients versus 14 (8%) of 186 anti‐TIF1γ–negative DM patients were positive for anti‐CCAR1 antibodies (P < 0.001). Anti‐CCAR1 antibodies were not detected in any of the 32 serum samples from healthy controls, and were present at very low frequencies in the sera of patients with other rheumatic diseases: 1 (2.3%) of 44 patients with anti–hydroxymethylglutaryl‐coenzyme A reductase–positive necrotizing myopathy, 1 (2.3%) of 44 patients with inclusion body myositis, and 3 (6.5%) of 46 patients with systemic lupus erythematosus were positive for anti‐CCAR1 antibodies. Upon examining data on occurrence of cancer from the onset of DM onward, the observed number of cancers diagnosed in anti–TIF‐1γ–positive DM patients was significantly greater than expected in both cohorts, with a standardized incidence ratio (SIR) of 3.49 (95% confidence interval 95% CI 2.39–4.92) in the Johns Hopkins cohort and a SIR of 4.54 (95% CI 3.04–6.52) in the Stanford cohort (each P < 0.001). DM patients who were both anti‐TIF1γ positive and anti‐CCAR1 positive had lower SIRs for cancer, with a SIR of 1.78 (95% CI 0.77–3.51) (P = 0.172) in the Johns Hopkins cohort and a SIR of 1.61 (95% CI 0.44–4.13) (P = 0.48) in the Stanford cohort.
Conclusion
Anti‐CCAR1 autoantibodies are specific for anti‐TIF1γ–positive DM. Their presence in anti‐TIF1γ–positive patients attenuates the risk of cancer to a level comparable to that seen in the general population.
Objective
We undertook this study to 1) determine the sensitivity of the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria for ...idiopathic inflammatory myopathies (IIMs) to properly classify myositis‐specific autoantibody (MSA)–positive myositis patients, 2) describe the phenotype and muscle involvement over time in different MSA‐positive patients, and 3) compare MSA subgroups to EULAR/ACR criteria–defined myositis subgroups for their capacity to predict clinical phenotypes in patients with IIMs.
Methods
The study included 524 MSA‐positive myositis patients from the Johns Hopkins Myositis Center. Each patient was classified using the EULAR/ACR classification criteria. Patient phenotypes were summarized using factor analysis of mixed data (FAMD). We compared the ability of MSAs to that of the EULAR/ACR classification subgroups to predict the phenotype of patients by applying the Akaike information criterion (AIC) and the Bayesian information criteria (BIC) to the linear regression models.
Results
Overall, 91% of MSA‐positive patients met the EULAR/ACR criteria to be classified as having myositis. However, 20% of patients with anti–hydroxymethylglutaryl‐coenzyme A reductase (anti‐HMGCR) and 50% of patients with anti–PL‐7 were incorrectly classified as not having myositis. Furthermore, ~10% of patients with anti–signal recognition particle (anti‐SRP) and patients with anti‐HMGCR were misclassified as having inclusion body myositis. FAMD demonstrated that patients within each MSA‐defined subgroup had similar phenotypes. Application of both the AIC and BIC to the linear regression models revealed that MSAs were better predictors of myositis phenotypes than the subgroups defined by the EULAR/ACR criteria.
Conclusion
Although the EULAR/ACR criteria successfully classified 91% of MSA‐positive myositis patients, certain MSA‐defined subgroups, including those with autoantibodies against HMGCR, SRP, and PL‐7, are frequently misclassified. In myositis patients with MSAs, autoantibodies outperform the EULAR/ACR‐defined myositis subgroups in predicting the clinical phenotypes of patients. These findings underscore the need to include MSAs in a revised myositis classification scheme.
ABSTRACT
Introduction: To characterize cellular infiltrates in muscle biopsies from patients with anti‐3‐hydroxy‐3‐methyl‐gulatryl‐CoA reductase (HMGCR)‐associated myopathy. Methods: Biopsies from 18 ...anti‐HMGCR myopathy and 7 control dermatomyositis patients were analyzed. Results: CD4+ and CD8+ T‐cells were scattered within the endomysium in 50% of anti‐HMGCR biopsies. All anti‐HMGCR biopsies included increased endomysial and/or perivascular CD163+ M2 macrophages; CD11c+ M1 macrophages were present in 18.8%. CD123+ plasmacytoid dendritic (PD) cells were observed within the endomysium and perivascular spaces in 62.5% of anti‐HMGCR biopsies. Membrane attack complex was deposited on endothelial cells in 50% and on the sarcolemma of nonnecrotic muscle fibers in 85.7% of anti‐HMGCR cases. Major histocompatibility complex class I antigen was up‐regulated in 87.5% of the anti‐HMGCR cases. Conclusions: In addition to necrosis, scattered CD4+, CD8+, and PD cells are characteristic of anti‐HMGCR myopathy. Predominant M2 polarization suggests infiltrating macrophages are more likely to be involved with tissue repair than destruction. Muscle Nerve, 2015. Muscle Nerve 52: 189–195, 2015
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