TNF-Induced Lupus. A Case-Based Review

: Nowadays, tumor necrosis factor alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, among them, drug-induced lupus (DIL). Case Presentation: A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone, was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti-Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued and she was treated successfully with prednisone plus local calcineurin inhibitors. Conclusion: Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.

Strong Association of the Myriad Discrete Speckled Nuclear Pattern With Anti-SS-A/Ro60 Antibodies: Consensus Experience of Four International Expert Centers

IntroductionThe morphological patterns in indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA) reflect the autoantibodies in the sample. The International Consensus on ANA Patterns (ICAP) classifies 30 relevant patterns (AC-0 to AC-29). AC-4 (fine speckled nuclear pattern) is associated to anti-SS-A/Ro, anti-SS-B/La, and several autoantibodies. Anti-SS-A/Ro samples may contain antibodies to Ro60 and Ro52. A variation of AC-4 (herein designated AC-4a), characterized by myriad discrete nuclear speckles, was reported to be associated with anti-SS-A/Ro. The plain fine speckled pattern (herein designated AC-4b) seldom was associated with anti-SS-A/Ro. This study reports the experience of four expert laboratories on AC-4a and AC-4b.MethodsAnti-Ro60 monoclonal antibody A7 was used to investigate the HEp-2 IFA pattern. Records containing concomitant HEp-2 IFA and SS-A/Ro tests from Durand Laboratory, Argentina (n = 383) and Fleury Laboratory, Brazil (n = 144,471) were analyzed for associations between HEp-2 IFA patterns and disease-associated autoantibodies (DAA): double-stranded DNA, Scl-70, nucleosome, SS-B/La, Sm, and U1-RNP. A total of 381 samples from Dresden Technical University (TU-Dresden), Germany, were assayed for HEp-2 IFA and DAA.ResultsMonoclonal A7 recognized Ro60 in Western blot and immunoprecipitation, and yielded the AC-4a pattern on HEp-2 IFA. Analyses from Durand Laboratory and Fleury Laboratory yielded compatible results: AC-4a was less frequent (8.9% and 2.7%, respectively) than AC-4b (26.1% and 24.2%) in HEp-2 IFA-positive samples. Reactivity to SS-A/Ro occurred in 67.6% and 96.3% of AC-4a-pattern samples against 23% and 6.8% of AC-4b pattern samples. Reciprocally, AC-4a occurred in 24% and 47.1% of anti-SS-A/Ro-positive samples, and in 3.8% and 0.1% of anti-SS-A/Ro-negative samples. Data from TU-Dresden show that the AC-4a pattern occurred in 69% of 169 anti-SS-A/Ro-monospecific samples (62% of all anti-SS-A/Ro-positive samples) and in 4% of anti-SS-A/Ro-negative samples, whereas anti-SS-A/Ro occurred in 98.3% of AC-4a samples and in 47.9% of AC-4b samples. In all laboratories, coexistence of anti-SS-B/La, but not other DAA, in anti-SS-A/Ro-positive samples did not disturb the AC-4a pattern. AC-4a was predominantly associated with anti-Ro60 antibodies.ConclusionsThis study confirms the association of AC-4a pattern and anti-SS-A/Ro in opposition to the AC-4b pattern. The results of four international expert laboratories support the worldwide applicability of these AC-4 pattern variants and their incorporation into ICAP classification under codes AC-4a and AC-4b, respectively. The AC-4 pattern should be maintained as an umbrella pattern for cases in which one cannot discriminate AC-4a and AC-4b patterns. The acknowledgment of the AC-4a pattern should add value to HEp-2 IFA interpretation.

AB0697 ANTI-SARS-COV-2 ANTIBODIES AND AUTOANTIBODIES IN COVID-19 PATIENTS SURVIVED AFTER ICU ADMISSION, 6 MONTHS LATER

Background:We1 and others2 have previously shown that ICU admitted patients with COVID-19 developed high titers of anti-SARS-CoV-2 antibodies, but also autoantibodies, some of which are pathogenic. We re-evaluated 8 patients of those survived after admission to the ICU of Evangelismos Hospital of Athens -1st Department of Internal Medicine, Medical School, NKUA3 6 months later. We did not know whether these autoantibodies still exist, are associated with COVID-19 or with ARDS as described after septic shock4.Objectives:To investigate the presence and titers of anti-SARS-CoV-2 antibodies and autoantibodies in patients survived after COVID-19 ICU stay, in the ICU and 6 months later.Methods:Case series to evaluate titers of anti-SARS-CoV-2 antibodies, specificities of autoantibodies as well as clinical features in ICU admitted COVID-19 patients, initially and 6 months after their discharge. Evaluation of current clinical status included evaluation of lung, heart, kidney, central and peripheral nervous system and mental status using standardized methods. Methods for detection of anti-SARS-CoV-2 antibodies and autoantibodies were described in our previous report1.Results:We had initially evaluated1 29 ICU admitted COVID-19 patients’ files and sera, of which 4 had been already died during serum evaluation. Six more patients died thereafter. Out of 19 having been discharged, 8 were willing to be re-evaluated. On second evaluation 6 months later, serum anti-SARS-CoV-2 antibodies were highly positive, although at lower titers compared to the titers at disease onset (median [range]) 8.705 (range: 7.95-9.56) vs 6.640 (range: 6.29-6.76), p=0.0002, Mann-Whitney test. Initially 3 out of 8 patients expressed antinuclear antibodies (ANA) at titers 1/160, 1/320 and 1/320 with a fine speckled pattern with the second patient also expressing at a titer of 1/160, antimitochondrial (AMA) antibodies. Six months later the same patients and not anyone else expressed ANA of the same pattern at titers 1/640, 1/160 and 1/160 respectively. Two patients with 1/20 p-ANCA and 1/640 c-ANCA initially, lost their respective autoantibodies after 6 months. One patient initially negative for IgM anti-β2GPI became positive at low titer and an initially positive became negative. One patient initially positive for anti-Ro60 antibody continued to be positive 6 months later. One patient initially negative developed anti-Tg antibodies and 3 patients initially positive for anti-TPO antibodies remained positive 6 months later.Conclusion:Patients with COVID-19 survived after ICU admission still retain high titers of anti-SARS-CoV-2 antibodies but significantly lower that at disease onset, but they tend to lose autoantibodies with pathogenic potential.References:[1]Vlachoyiannopoulos P et al, Ann Rheum Dis 2020,[2]2. Wang EY et al, medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20247205[3]National and Kapodistrian University of Athens, Athens, Greece[4]Burbelo et al. Journal of Translational Medicine 2010Disclosure of Interests:None declared

Heresenes's Short Life under a "Starry Night"

Heresenes is a mummified 25th Dynasty (ca. 746–653 B.C.) Egyptian woman from Luxor, Egypt. Nondestructive evaluation through computerized tomography (CT) showed a failed attempt at excerebration, leaving Heresenes’s meninges and brain in situ. The brain structure shows numerous millimetric dense calcific nodules, a CT brain pattern dubbed “starry night,” which is consistent with a diagnosis of neurocysticercosis in a nodular calcified stage. A similar speckled pattern in the upper spinal cord and in the heart supports the identification of a disseminated stage of this parasitic disease. If this were the case, then this would be the oldest documented case of this disease known in ancient Egypt, and the first nondestructive radiological diagnosis of it in a completely wrapped Egyptian mummy.Heresenes est une femme Égyptienne momifiée de la 25e dynastie (c. 746 aC–653 aC). L'évaluation non destructive par tomodensitométrie (TDM) a montré l'échec de la tentative d'excérébration, laissant les méninges et le cerveau d'Heresenes in situ. La structure cérébrale présente de nombreux nodules calciques denses millimétriques, une apparence en TDM surnommé «nuit étoilée», ce qui est cohérent avec un diagnostic de neurocysticercose dans un stade nodulaire calcifié. Un motif similaire dans la moelle épinière supérieure et dans le coeur soutien l´identification dun processus disséminé de cette maladie parasitaire. Si tel était le cas, ce serait le plus ancien cas documenté de cette maladie connue dans l'Égypte ancienne, et le premier diagnostic radiologique non destructif dans une momie égyptienne complètement enveloppée.

Rowell’s syndrome: a rare but distinct entity in rheumatology

Rowell’s syndrome is a rare disorder characterised by an association of lupus erythematosus with erythema multiforme (EM)-like skin lesions. EM as the initial clinical presentation of systemic lupus erythematosus is also atypical and even rarer. We report the case of an 18-year-old girl admitted to our hospital with fever and polyarthralgia along with multiple discrete ill-defined target lesions with crust formation over forehead, cheek, external ears, scalp, upper chest and back (predominantly over sun-exposed areas) with ulceration over hard palate. Investigations revealed pancytopaenia, a positive rheumatoid factor, positive antinuclear antibody with a speckled pattern, anti-Smith antibody and strongly positive anti-Ro. Patient was diagnosed with Rowell’s syndrome as per clinical and laboratory features. Majority of skin lesions including oral ulcerations subsided gradually after treatment with steroids and hydroxychloroquine.

Recognising the spectrum of scleromyositis: HEp-2 ANA patterns allow identification of a novel clinical subset with anti-SMN autoantibodies

ObjectiveTo describe systemic sclerosis (SSc) with myopathy in patients without classic SSc-specific and SSc-overlap autoantibodies (aAbs), referred to as seronegative scleromyositis.MethodsTwenty patients with seronegative scleromyositis diagnosed by expert opinion were analysed retrospectively for SSc features at myositis diagnosis and follow-up, and stratified based on HEp-2 nuclear patterns by indirect immunofluorescence (IIF) according to International Consensus of Autoantibody Patterns. Specificities were analysed by protein A−assisted immunoprecipitation. Myopathy was considered an organ involvement of SSc.ResultsSSc sine scleroderma was a frequent presentation (45%) at myositis diagnosis. Myositis was the most common first non-Raynaud manifestation of SSc (55%). Lower oesophagal dysmotility was present in 10 of 11 (91%) investigated patients. At follow-up, 80% of the patients met the American College of Rheumatology/EULAR SSc classification criteria. Two-thirds of patients had a positive HEp-2 IIF nuclear pattern (all with titers ≥1/320), defining three novel scleromyositis subsets. First, antinuclear antibody (ANA)-negative scleromyositis was associated with interstitial lung disease (ILD) and renal crisis. Second, a speckled pattern uncovered multiple rare SSc-specific aAbs. Third, the nuclear dots pattern was associated with aAbs to survival of motor neuron (SMN) complex and a novel scleromyositis subset characteriszed by calcinosis but infrequent ILD and renal crisis.ConclusionsSSc skin involvement is often absent in early seronegative scleromyositis. ANA positivity, Raynaud phenomenon, SSc-type capillaroscopy and/or lower oesophagal dysmotility may be clues for scleromyositis. Using HEp-2 IIF patterns, three novel clinicoserological subsets of scleromyositis emerged, notably (1) ANA-negative, (2) ANA-positive with a speckled pattern and (3) ANA-positive with nuclear dots and anti-SMN aAbs.

Eastern Bluebirds (Sialia sialis) use color patterning, but not the colors themselves, as a cue to eject interspecific parasitic eggs

Brood parasitism results in substantial costs to hosts, yet not all species eject foreign eggs. Because the costs of mistakenly ejecting one’s own eggs are high, selection may favor ejection behavior only if it is unlikely a host will incorrectly eject her own eggs. Eastern Bluebirds (Sialia sialis) are currently subject to relatively low levels of interspecific brood parasitism but still sometimes eject parasitic eggs. Therefore, we tested which visual cues they use to eject foreign eggs with the prediction that only the most dissimilar eggs would be ejected, reducing the likelihood of a female making a mistake. House Sparrows (Passer domesticus), which occasionally parasitize bluebirds, lay eggs that have an off-white ground color with brown speckling. Therefore, to test which colors or patterns allow for discrimination of parasitic eggs, we generated 3-dimensional (3D)-printed model House Sparrow eggs and painted them entirely off-white, entirely brown, half off-white and half brown, or off-white with brown speckling. We then sequentially placed these 4 different model eggs in the nests of Eastern Bluebirds, with each nest receiving all treatments over the course of 4 days. After watching females enter and leave the nest box just one time after placement of the model egg, we found that speckled eggs were ejected half the time (7 of 14 nests), while no other treatment was ejected more than 3 times. Thus, Eastern Bluebird females eject eggs based primarily on color patterning (i.e. a speckled pattern) rather than coloration per se, and that they can do so quickly, as the average female had removed the model egg within 6 min of entering the nest. Because Eastern Bluebirds do not lay speckled eggs, but some brood parasites do (e.g., House Sparrows, Brown-headed Cowbirds [Molothrus ater]), selection may specifically favor ejection of eggs with a speckled pattern, not just eggs that have within-egg color contrasts.