All 4 patients were French Canadian. There were 3 women and 1 man, with ages at the time of referral ranging from 35 years to 70 years. In the 4 patients, the dominant clinical feature at referral was AIM requiring immunosuppressive therapy. According to Bohan and Peter criteria, in 3 patients (LGL, BP, and AL) myositis could be classified as “definite polymyositis” whereas in patient DGP criteria for “possible polymyositis” were fulfilled.5 However, a more current diagnosis is overlap myositis, as recently defined.50 As shown in Table 1 , myositis was severe in patients LGL, BP, and AL, and less severe in patient DGP. In the former 3 patients, myositis was characterized by symmetric and proximal weakness with muscle strength graded 3/5 or 3.5/5 associated with elevated serum CK levels ranging from 1765 to 4836 U/L. Electromyography showed myositic abnormalities as defined by Bohan and Peter criteria.5 Quadriceps muscle biopsies, performed before the recent ENMC criteria,19 were consistent with idiopathic inflammatory myopathy as defined by Bohan and Peter.5 None of the patients was exposed to statin therapy.
Myositis in patients LGL, BP, and AL required high daily doses of prednisone (1 mg/kg), plus methotrexate (MTX) or azathioprine as a second immunomodulating agent to induce remission (see Table 1 ). In patients LGL and BP, the myositis was refractory, that is, initial corticosteroid therapy alone failed to induce remission, necessitating the addition of MTX (LGL) or azathioprine (BP).50 Given this aggressive profile of anti-NPC associated myositis, patient AL was treated from the outset with both corticosteroids and MTX. In all 3 patients, the myositis course was chronic, that is, requiring long-term corticosteroid treatment (daily prednisone >5 mg) and second-line therapy.50 Both patients LGL and AL experienced myositis relapses when prednisone was discontinued, necessitating reintroduction of this drug. The myositis course and therapy of patients LGL and BP are illustrated longitudinally in Figure 2.
In the 4th patient (DGP), myositis was characterized by grade 4/5 proximal muscle weakness, oropharyngeal dysphagia, and mild serum aldolase and CK elevation. Remission was induced by prednisone 20 mg daily alone. No myositis relapse occurred over follow-up. Whether this favorable course was influenced by MTX introduced later for rheumatoid arthritis is unknown.
Other Overlap Syndrome Features Associated With Anti-NPC
In addition to myositis, these patients shared several overlap syndrome features, including Raynaud phenomenon (n = 3 patients) and trigeminal neuropathy (n = 2 patients) (see Table 1 ). In patient DGP, trigeminal neuropathy preceded myositis by 4 years, whereas in patient LGL bilateral trigeminal neuropathy occurred during the 6 months preceding myositis. In 3 patients, weight loss (3.6–7.3 kg) preceded the diagnosis of myositis by several weeks.
Erosive, rheumatoid factor-positive, anti-CCP positive, and symmetric polyarthritis consistent with rheumatoid arthritis was present in 3 patients (BP, DGP, and AL) (see Table 1 ). In patient BP, rheumatoid arthritis was associated with olecranial nodules and ulnar deviation. In 2 patients, arthritis preceded myositis by several years, whereas in patient DGP, a cigarette smoker, arthritis onset occurred 3 years after myositis. Interstitial lung disease (n = 2) was mild and characterized by discrete fibrosing alveolitis on chest radiogram and pulmonary function tests showing a restrictive pattern for patient BP and a DLCO of 67% for patient DGP. A single patient, DGP, developed sicca symptoms with predominant xerophthalmia.
None of these patients showed features of SLE, or skin features of dermatomyositis or systemic sclerosis. Serial nailfold capillary microscopy remained normal in all patients.
Anti-NPC Overlap Syndrome May Be Associated With a Good Overall Prognosis
Although myositis required corticosteroids and a second immunomodulating agent for therapeutic control, myositis eventually subsided in all patients (see Table 1 ). No life-threatening systemic complication nor cancer have occurred at prolonged follow-up, with 100% survival at last visit (mean follow-up 19.5 yr, range 12–26 yr). Taken altogether, these data suggest that anti-NPC myositis-overlap syndrome may be associated with a good overall prognosis. However the number of patients reported herein is small and more patients will need to be studied.
Anti-NPC Parallel Myositis Activity
High titers of anti-NPC, ranging from 1:1280 to 1:10,240, were present at myositis diagnosis in sera from all 4 patients (Table 2). Anti-NPC titers fluctuated in parallel with the serum CK level in patients LGL, BP, and AL. This is illustrated in Figure 2 for patients LGL and BP. For both patients, the highest anti-NPC titer correlated with the highest CK level, followed by a progressive fall of anti-NPC to undetectable levels with treatment-induced remission. In patient AL, a similar decrease in anti-NPC titer in parallel with decreasing myositis activity was observed in consecutive serum samples over 5 months. Interestingly, in patient LGL a striking rise of anti-NPC coincided with clinical and enzymatic myositis relapse following discontinuation of prednisone and MTX because of remission (Figure 2A). In patient DGP, who was not treated with aggressive immunosuppression, anti-NPC titers remained elevated over time.
Anti-NPC Autoantibody Is Found Only in Overlap Myositis Sera
Anti-NPC were present in 4 (4%) patients of our cohort of 100 consecutive patients with AIM52 (Table 3). Anti-NPC were not found in sera from 393 adult patients with systemic sclerosis (n = 112), systemic lupus erythematosus (n = 94), rheumatoid arthritis (n = 45) (these diseases defined according to ACR criteria), MCTD (n = 35), autoimmune hepatitis (n = 13), psoriatic arthritis (n = 19), ankylosing spondylitis (n = 22), primary gout (n = 33), or primary osteoarthritis (n = 20), nor were they observed in sera from 62 normal adults. By 2-sided Fisher exact test, the association of anti-NPC with AIM was highly significant: for AIM versus all disease and normal controls, OR 42.4 (95% CI 2.3–796), p = 0.001; AIM vs disease controls only, OR 36.7 (95% CI 1.96–688), p = 0.0016.
The Predominant Anti-NPC Isotype is IgG
The anti-NPC isotype present in all 4 patients at myositis diagnosis was IgG (see Table 2). In patients LGL and BP, only IgG anti-NPC was present. Patient DGP also expressed strong IgA anti-NPC, whereas patient AL expressed IgM as well as IgA anti-NPC, albeit at lower intensity than IgG.
Lack of Other IgG Autoantibody Connective Tissue Disease Marker in Anti-NPC Sera
No other IgG autoantibody marker for a defined connective tissue disease or to an overlap syndrome was identified in anti-NPC positive sera (see Table 2). Specifically, autoantibodies were absent to synthetases (Jo-1, PL-7, PL-12, OJ, EJ, KS, Tyr, and Zo), SRP, systemic sclerosis-specific autoantigens (CENP-B, topoisomerase I, RNA polymerase III, and Th/To), and to autoantigens associated with MCTD and systemic sclerosis or SLE in overlap (U1-U2-U3-U5RNP, PM-Scl, and Ku). Anti-p155/140, anti-MDA5, and anti-MJ were also negative.
Anticardiolipin and lupus anticoagulant antibodies were absent.
Heterogeneity of Nucleoporin Autoantigens
Nup358/RanBP2, a major component of the cytoplasmic filaments of the NPC is the autoantigen reactive with anti-NPC from patients DGP and AL (unpublished data and references53,54) (see Table 2). In addition, DGP serum reacted with gp210 but only by LIA. By immunoblotting, DGP serum did not react at all with gp210 and by immunogold electron microscopy, the NPC localization was typical of Nup358/RanBP2 and not that of gp210.53,54
LGL serum was previously shown to react by immunoblotting with polypeptides of 200 kD and 130 kD enriched in nuclear envelopes.10 In addition, LGL serum reacted by ALBIA with Nup62. Last, patient BP anti-NPC serum at a dilution of 1:500 reacted by immunoblotting with a single band of 90 kD protein in HeLa cells, rat cells and in Xenopus laevis and Pleurodele oocyte nuclear envelopes.9,27 By immunoelectron microscopy, anti-NPC from patient BP reacted with intranuclear filaments attached to NPCs. Taken together, these features suggested that patient BP serum recognized a novel nup, nup90, distinct from central domain-localized nup95 and intranuclear filament-associated nup153, as previously reported.9,27
Given that autoantibodies to gp210 and nup p62 have been associated with PBC, sera from the 4 patients were also tested for reactivity against a panel of autoantigens associated with autoimmune liver disease (see Table 2). All sera were negative except for DGP serum, which was positive for anti-mitochondrial M2 antibodies, but not for anti-M2–3E(BPO). Of interest, all patient sera were negative for antimitochondrial and anti-smooth muscle antibodies by indirect immunofluorescence on mouse tissues and for mitochondrial fluorescence on HEp-2 cells. Because of mildly elevated serum transaminases, and before detection of raised serum CK and the subsequent diagnosis of myositis, patient LGL had a liver biopsy, which was normal (see Table 1 ). Neither patient LGL nor patient DGP have shown any clinical or enzymatic evidence of liver disease over 26 years and 23 years of follow-up, respectively. In patient LGL, an abdominal ultrasound done 26 years after myositis diagnosis because of longstanding MTX therapy revealed no evidence of liver disease.
By PCR-SSOP, the DQA1*0501 allele was shared by all 4 patients (100%) with anti-nup (Table 4). The DPA1*0103 allele was also shared by all patients. Three of the patients also carried the DRβ3*0101 allele. The DRB1*0301 allele was identified in 2 patients.
To our knowledge, this is the first report describing the association between anti-NPC autoantibodies and an overlap syndrome with prominent myositis in a patient population of connective tissue diseases sharing a common ethnogeographic background. This clinical subset accounts for 4% of our cohort of French Canadian patients with AIM.50 Subsetting of patients with AIM according to their autoantibody markers is increasingly used by clinicians to diagnose more accurately these diseases, individualize their treatment and determine their prognosis.12,22,49 Thus, the shared phenotypic, immunogenetic and ethnogeographic characteristics in our patients with anti-NPC raise the question whether a novel AIM-overlap subset, the “anti-nup syndrome,” may be recognized by the presence of these autoantibodies.
Several data strongly support the concept of an “anti-nup syndrome” (Table 5). First, patients with a high titer of IgG anti-NPC autoantibodies share a similar clinical overlap syndrome. The 4 patients have in common prominent myositis as well as rheumatoid factor positive, anti-CCP positive and erosive rheumatoid arthritis, Raynaud phenomenon, mild interstitial lung disease and trigeminal neuralgia (see Table 5). The myositis features fulfilled proposed criteria for overlap myositis.50 At follow-up, no SLE manifestations or cutaneous features of dermatomyositis or systemic sclerosis were noted. Long-term survival was excellent and the overall prognosis was good.
Second, the immunologic marker shared by these patients, that is, anti-NPC, appears selectively expressed, that is, no other myositis specific autoantibody, such as antisynthetases, nor any marker autoantibody associated with overlap myositis, such as anti-U1RNP, anti-U3RNP, anti-Ku, or anti-PM-Scl was identified.22,50 In fact, no other IgG autoantibody marker for a connective tissue disease was detected other than anti-NPC.
Third, all 4 patients shared the MHC Class II allele DQA1*0501, the frequency of which is increased in white patients with AIM, most strikingly those with myositis specific autoantibodies.1,34,42 Two of the patients also carried a linked allele, DRB1*0301. These unexpected findings suggest that patients with anti-NPC share immunogenetic disease susceptibility and, moreover, that shared and specific immunopathogenic mechanisms of disease are involved in these patients. Overall, the shared DQA1*0501 allele brings strong pathophysiologic support to the concept of an “anti-nup syndrome.”
Fourth, anti-NPC titers varied strikingly in parallel with myositis activity, suggesting a mechanistic relationship, as yet undefined, to the pathophysiology of the disease. Interestingly, a similar fluctuation with myositis activity has been observed with anti-Jo-1 autoantibodies, which are markers for another overlap myositis syndrome, the antisynthetase syndrome.29
Last, the molecular heterogeneity of nup autoantigens is reminiscent of the antigenic heterogeneity observed in the antisynthetase syndrome, where autoantibodies to 8 synthetase autoantigens have been identified.46,49 None of the 4 patients with anti-nup displayed an antisynthetase. Moreover, there are major clinical differences between the clinical features in our patients and antisynthetase syndrome manifestations, including in the latter more severe interstitial lung disease, fever, dermatomyositis cutaneous features and a poorer prognosis with decreased survival.52 Thus, taken altogether, the data are consistent with an apparent “anti-nup syndrome” in our patient population.
This is the first report on anti-NPC autoantibodies encompassing a large group of patients from a uniform ethnogeographic background and with well-defined connective tissue diseases who were systematically screened by indirect immunofluorescence for the characteristic NPC fluorescent ANA pattern. Other reports are mostly case reports and have major methodologic differences with the present study, including absence of controls and lack of long-term follow-up. Anti-NPC were reported in 10 patients with connective tissue diseases from various ethnogeographic backgrounds.11,25,26,30 Anti-gp210 was noted in 2 patients with rheumatoid arthritis and Sjögren syndrome, respectively.25 Anti-p62 was reported in 4 patients with Sjögren syndrome,30 2 patients with rheumatoid arthritis,30 and a single MCTD patient with myositis requiring immunosuppressive treatment.26 Last, autoantibodies to Nup153 were reported in a single SLE patient.11 The few controlled studies are cross-sectional and focused on PBC and reactivity with a single nup. For example, in a French study of anti-gp210, 25% (n = 72) of 285 patients with PBC expressed the antibody whereas of 116 control patients with SLE, seropositive rheumatoid arthritis or systemic vasculitis, a single patient was positive for anti-gp210, for whom follow-up was not available.3
In summary, the relationship, if any, between these reports and the present study cannot be ascertained given methodologic differences, including lack of well-defined and large connective tissue disease control groups, testing restricted to reactivity with a single nup, lack of clinical phenotype description and/or absence of long-term follow-up. In addition, none of these patients was evaluated specifically for the anti-Nup358/RANBP2, anti-p90, or anti-p200/p130 specificities observed in the present study. Therefore, it will be important to study the frequency of anti-NPC as well as the associated phenotypes, antigenic specificities and immunologic features in other large international series of patients with connective tissue diseases, and particularly among patients with an overlap myositis syndrome.
Several nup specificities were identified by sera from our patients, indicating that the nup autoantigens are heterogeneous. Polypeptides of 200 kd and 130 kd were detected by LGL serum on immunoblots of nuclear envelope preparations.10 LGL serum also reacted with Nup62 by ALBIA.31,42 Nup358/RANBP2 was recognized by 2 patient sera (DGP and AL). A 180 kd polypeptide was initially identified as the autoantigen targeted by DGP serum and was called Nup180.53 Later, Nup180 was identified as a Nup358/RanBP2 fragment.54 Nup358/RanBP2 is a major component of the NPC cytoplasmic filaments and is essential for nuclear transport, mitosis and cell viability.16,54 In the search for the antigenic specificities associated with anti-NPC in our patients, we screened their sera for anti-gp210 and anti-Nup62. Interestingly, DGP serum (but not AL serum) reacted with gp210. However, by immunoblotting DGP serum did not react at all with gp210 and by immunogold electron microscopy, the NPC localization of Nup358/RanBP2 was distinct from gp210.53,54 Taken altogether, these data suggest that cross-reactive epitopes may account for the reactivity of DGP serum with gp210. Indeed, partial amino acid sequence homology was identified between Nup358/RanBP2 and gp210. For example, the Nup358/RanBP2 LLLK and SELAAL sequences are similar, respectively, to the gp210 LELK and STLAGL sequences.
The present report expands to the nuclear envelope, and specifically to the NPCs, the cellular compartments where autoantigens associated with overlap myositis syndromes are localized. Thus far, this had been restricted to the nucleus and to the cytoplasm. Autoantibodies to the nuclear autoantigens U1RNP, U3RNP, Ku and PM-Scl are associated with various overlap myositis syndromes. In contrast, autoantibodies to the cytoplasmically localized synthetases and MDA5 autoantigens are associated, respectively, with the antisynthetase syndrome and with a dermatomyositis overlap syndrome. The latter syndromes are phenotypically distinct from the former ANA-associated syndromes and, in turn, appear distinct from anti-nup syndrome features,15,49 although a larger number of patients with connective tissue diseases and anti-nup autoantibodies will need to be studied.
The autoantigens identified by our patient sera are also intriguing in light of the differential localization of these proteins within the NPC structure. Nup358/RanBP2 is found at the cytoplasmic face of the NPC while gp210 is part of the central framework.18a,27 Nup62 is a complex of proteins (p62, p60, and p54) also localized in the central framework composing the central channel.18a,21 In contrast, Nup90, identified using anti-NPC serum from patient BP, localizes at the intranuclear NPC-attached filaments.27 The exact relationship between the molecular identity and cellular localization of these autoantigens and the corresponding overlap myositis syndromes remains to be deciphered.
Several features of the autoimmune response that characterizes anti-NPC autoantibodies in our patients deserve comment (see Table 5). Anti-NPC were predominantly of IgG isotype and present in high titers at diagnosis. Anti-NPC varied in parallel with myositis activity or persisted in high titers over time and were directed to highly conserved antigenic determinants within the cytoplasmic, nuclear or central framework of the NPC. Taken together, these features suggest that nup autoantigens themselves drive the anti-nup autoimmune response. The absence of other connective tissue disease marker autoantibodies is consistent with antigen selectivity and a highly focused immune response. Thus, anti-nup autoantibodies appear antigen-driven and display some features of pathogenic autoantibodies.32
The initiating event that trigger anti-nup immune responses is unknown. In PBC, molecular mimicry following hepatitis B virus infection was evoked as a potential mechanism, as certain nup amino acid sequences display similarity with hepatitis B virus DNA polymerase.13 However, PBC patient sera did not react with the shared epitopes.13 None of our 4 patients with anti-NPC had serologic evidence of hepatitis B virus infection. Mimicry of bacterial antigenic determinants has also been proposed since the predominant autoepitope of gp210 recognized by anti-gp210 from 25 PBC patients is homologous to Escherichia coli mut Y and Salmonella typhimurium mut B gene products.33 However, further study revealed that mut Y gene product was not recognized by anti-gp210 autoantibodies.8
Finally, although no direct mechanistic link between anti-NPC and myositis is established, a specific pathophysiologic link between nups and striated skeletal muscle is suggested by the correlation between anti-NPC titers and myositis activity. Interestingly, other nuclear envelope components are known to be critical in muscle disease. For example, emerin and lamin A/C gene mutations are associated with specific muscular dystrophies.7,44 Furthermore, Asally et al2 have identified a key role for Nup358 in skeletal myogenesis. More studies are needed to clarify the pathophysiologic link between anti-nup autoantibodies and the “anti-nup syndrome.”
The authors thank Gemma Perez and Haiyan Hou for laboratory assistance and Carole Blouin for secretarial assistance.
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