Does Tocilizumab Influence Ophthalmic Outcomes in Giant Cell Arteritis?

Background: Despite appropriate use of corticosteroids, an important minority of patients with giant cell arteritis (GCA) develop progressive vision loss during the initial stages of the disease or during corticosteroid tapering. Tocilizumab is the only clearly effective adjunctive treatment to corticosteroids in the management of GCA, but questions regarding its efficacy specifically in the neuro-ophthalmic population and its role in mitigating vision loss have not been broached until recently. Evidence acquisition: The authors queried Pubmed using the search terms "GCA" and "tocilizumab" in order to identify English-language publications either explicitly designed to evaluate the influence of tocilizumab on the ophthalmic manifestations of GCA or those which reported, but were not primarily focused on, ophthalmic outcomes. Results: Recent retrospective analyses of populations similar to those encountered in neuro-ophthalmic practice suggest that tocilizumab is effective in decreasing the frequency of GCA relapse, the proportion of flares involving visual manifestations of GCA, and the likelihood of permanent vision loss. Data regarding the utility of tocilizumab to curtail vision loss at the time of diagnosis are limited to case reports. Conclusions: Compared with conventional corticosteroid monotherapy, treatment of GCA with both corticosteroids and tocilizumab may decrease the likelihood of permanent vision loss. Further prospective, collaborative investigation between rheumatologists and neuro-ophthalmologists is required to clarify the ophthalmic and socioeconomic impact of tocilizumab on the treatment of GCA.

State-of-the-Art Review Section Editors: Fiona Costello, MD, FRCP(C) Sashank Prasad, MD Does Tocilizumab Influence Ophthalmic Outcomes in Giant Cell Arteritis? Marc A. Bouffard, MD, Sashank Prasad, MD, Sebastian Unizony, MD, Fiona Costello, MD, FRCP(C) Background: Despite appropriate use of corticosteroids, an important minority of patients with giant cell arteritis (GCA) develop progressive vision loss during the initial stages of the disease or during corticosteroid tapering. Tocilizumab is the only clearly effective adjunctive treatment to corticosteroids in the management of GCA, but questions regarding its efficacy specifically in the neuro-ophthalmic population and its role in mitigating vision loss have not been broached until recently. Evidence Acquisition: The authors queried Pubmed using the search terms “GCA” and “tocilizumab” in order to identify English-language publications either explicitly designed to evaluate the influence of tocilizumab on the ophthalmic manifestations of GCA or those which reported, but were not primarily focused on, ophthalmic outcomes. Results: Recent retrospective analyses of populations similar to those encountered in neuro-ophthalmic practice suggest that tocilizumab is effective in decreasing the frequency of GCA relapse, the proportion of flares involving visual manifestations of GCA, and the likelihood of permanent vision loss. Data regarding the utility of tocilizumab to curtail vision loss at the time of diagnosis are limited to case reports. Conclusions: Compared with conventional corticosteroid monotherapy, treatment of GCA with both corticosteroids and tocilizumab may decrease the likelihood of permanent vision loss. Further prospective, collaborative investigation between rheumatologists and neuro-ophthalmologists is required to clarify the ophthalmic and socioeconomic impact of tocilizumab on the treatment of GCA. Journal of Neuro-Ophthalmology 2022;42:173–179 doi: 10.1097/WNO.0000000000001514 © 2022 by North American Neuro-Ophthalmology Society Department of Neurology (MAB), Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Department of Neurology (SP), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine (SU), Division of Rheumatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Marc A. Bouffard, MD, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue Boston, MA 02215; E-mail: [e-mail] Bouffard et al: J Neuro-Ophthalmol 2022; 42: 173-179 G iant cell arteritis (GCA) is neuro-ophthalmic emergency fraught with diagnostic and therapeutic dilemmas. Up to half of patients with GCA present with ophthalmic manifestations (Table 1) and, of those, up to 20% have none of the systemic symptoms commonly associated with GCA (Table 2) (1–24). Despite the protean manifestations of GCA and the diagnostic challenges which result, questions regarding optimal management arguably pose the most substantial dilemmas in caring for patients with GCA. Vision loss due to GCA-related arteritic anterior ischemic optic neuropathy (AAION) or central retinal artery occlusion (CRAO) is typically severe, meaningful recovery is infrequent, and involvement of the fellow eye is common within the days to weeks following presentation if treatment is not initiated (1,25–28). While it is clear that ophthalmic manifestations of GCA require rapid administration of high-dose corticosteroids, the optimal route and dose are guided by institutional experience and expert opinion rather than by robust prospective data (29–32). Despite swift intervention, a minority of patients develop further vision loss in the days following high-dose corticosteroid initiation (26,31). After achieving suppression of disease activity, the fundamental challenge in the management thereafter is to balance the risk of GCA relapse (which may pose a risk of further vision loss) with the iatrogenic harms associated with chronic corticosteroid therapy. Management of the ophthalmic manifestations of GCA has historically been achieved with corticosteroid monotherapy, subject to the shortcomings discussed above. Ideal improvements to the management of neuro-ophthalmic manifestations of GCA would include means to more effectively halt or reverse vision loss at presentation and to mitigate vision loss during corticosteroid tapering. Tocilizumab is a monoclonal antibody targeting the interleukin (IL)-6 pathway, which facilitates more rapid corticosteroid withdrawal and a higher probability of sustained GCA remission than possible with traditional corticosteroid 173 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 1. Neuro-ophthalmic manifestations of GCA Arteritic anterior ischemic optic neuropathy (most common) Central retinal artery occlusion Posterior ischemic optic neuropathy Ocular ischemic syndrome Amaurosis fugax (in w27% of patients with ocular manifestations of GCA)1 Diplopia GCA, giant cell arteritis monotherapy (33). While the impact of tocilizumab on systemic disease control in primarily rheumatologic population’s GCA is encouraging, the relative absence of data derived from neuro-ophthalmic populations and pertaining to visual outcomes has led to questions regarding its appropriate use in neuro-ophthalmic practice (33–35). Several recent publications have begun to address this gap in the literature, offering preliminary suggestions that the addition of tocilizumab to corticosteroid therapy may aid in the preservation of vision during corticosteroid tapering and possibly at the time of presentation with ophthalmic manifestations. Herein, we discuss recently published literature related to tocilizumab’s impact on vision preservation within the context of a brief overview of the pathophysiology, epidemiology, diagnosis, and treatment of GCA. PATHOPHYSIOLOGY OF GIANT CELL ARTERITIS AND THE ADVENT OF TOCILIZUMAB The granulomatous inflammation that characterizes GCA results from dysregulation of the acquired and innate immune systems. The underlying cause of GCA is unclear, although well-established risk factors (summarized in Table 3) for GCA include advancing age, Caucasian ethnicity, and female gender (36). Severity of disease also appears to be influenced by gender with treatment failure noted 5 times more often in women (37). The majority of patients with GCA are Caucasian and populations with Scandinavian ancestry are particularly susceptible (36,38). The association between racial background and GCA may be related to certain human leukocyte antigen class I and class II genes that are disproportionately represented in the Caucasian population and have been linked to GCA in genome-wide association studies (39–45). Contingent on these factors, the prevalence of GCA varies widely with estimates between 25 and 275 cases/100,000 persons $50 years depending of the geographic location (38,40–42). The inflammatory cascade in GCA is well defined. Dendritic cell activation and maturation in the arterial tunica adventitia leads to recruitment of CD4+ T cells that differentiate into T-helper (Th) 1 and Th17 cells, which avoid the homeostatic downregulation by T-regulatory cells seen in patients without GCA (46). Cytokines derived from activated T cells (e.g., IL-17 and interferon-g) stimulate macrophages, which acquire a proinflammatory phenotype with resulting destruction of the arterial internal elastic lamina, macrophage fusion into “giant cells”, and the production of further proinflammatory mediators, including IL-6 (47,48). Recognition of the central role of IL-6 in GCA pathogenesis and therefore as a potential target for therapeutic modulation was derived from data reporting its upregulation in serum and affected tissue in patients with GCA as well as its capacity to serve as a marker for disease activity (49–52). Tocilizumab is a humanized immunoglobulin G1 monoclonal antibody that targets the IL-6 receptor, impeding a key modulator of the inflammatory cascade in GCA. The Giant-cell Arteritis Actemra (GiACTA) trial clearly established tocilizumab’s efficacy in decreasing the probability of GCA relapse during corticosteroid taper (33). Inclusion criteria included a diagnosis of active GCA within 6 weeks of the baseline visit. Participants were enrolled into a 52-week double-blind trial with 4 arms (53): • Tocilizumab 162 mg weekly with a 26-week prednisone taper (N = 100). • Tocilizumab 162 mg every 2 weeks with a 26-week prednisone taper (N = 50). • Placebo with a 26-week prednisone taper (N = 50). • Placebo with a 52-week prednisone taper (N = 50). TABLE 2. Features suggestive of giant cell arteritis Cranial Manifestations Extracranial Manifestations Testing New headache Temporal allodynia Jaw claudication Palpable TA abnormalities Tongue pain Polymyalgia rheumatic Fever Malaise Weight loss Large artery involvement e.g., extremity claudication Temporal artery biopsy* ESR, CRP Hematocrit, platelets Serum IL-6 PET-CT MRI vessel wall Ultrasound *Provided .2 cm of temporal artery is biopsied, sensitivity is w85%, and yield of contralateral biopsy is likely ,5% (18–24). CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL, interleukin; PET-CT, positron emission tomography-computed tomography; TA, temporal artery. 174 Bouffard et al: J Neuro-Ophthalmol 2022; 42: 173-179 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 3. Risk factors for GCA 1. Advancing Age Nonlinear increase in risk with advancing age (after age 50 years) (38) 2. Caucasian ethnicity HLA class I and II genes disproportionately represented in Caucasian populations (36,39–45) 3. Female gender Women are twice as likely to develop GCA GCA, giant cell arteritis; HLA, human leukocyte antigen The primary end point of sustained remission at study Week 52 occurred in 53%–56% of GCA patients treated with tocilizumab plus a 26-week prednisone taper compared with only 14% of patients treated with placebo plus a 26-week prednisone taper and 18% who received placebo plus a 52week prednisone taper (33). Compared with corticosteroid monotherapy, the combination of tocilizumab and corticosteroids was associated with an improvement in health-related quality of life. Tocilizumab was well tolerated; however, patients with recent infection, latent tuberculosis, immunodeficiency, history of organ transplantation, and gastrointestinal abnormalities posing a risk of gastrointestinal perforation were excluded. In terms of safety, fewer patients developed serious adverse events in the weekly and every-other-weekly tocilizumab arm (15% and 14% respectively) than in the placebo groups that underwent 26- or 52-week prednisone taper (22% and 25%, respectively). Select caveats to the use of tocilizumab are outlined in Table 4. A ROLE FOR TOCILIZUMAB IN ADDRESSING TREATMENT DILEMMAS IN PATIENTS WITH OPHTHALMIC MANIFESTATIONS OF GIANT CELL ARTERITIS? The management of patients with neuro-ophthalmologic manifestations of GCA focuses on 2 challenges: 1. Optimizing rapid suppression of vasculitis at presentation, preventing further vision loss 2. Preventing vision loss during subsequent disease flares Historically, these goals have been pursued with corticosteroid monotherapy. Even after the GiACTA trial demonstrated the clear efficacy of tocilizumab in mitigating disease activity in GCA, its implications on neuroophthalmic practice remained unclear (33,34,54–57). The GiACTA trial was not designed or powered to analyze the impact of tocilizumab on ophthalmic outcomes. Only 1 patient developed AAION during corticosteroid tapering; notably, this patient was randomized into the every-otherweek tocilizumab arm, and vision loss was reversed with prompt administration of corticosteroids. It has been difficult for neuro-ophthalmologists to interpret the implications of the reversible vision loss in this single patient or the occurrence of vision loss in a participant receiving tocilizumab. Furthermore, administration of methylprednisolone at a dose of .100 mg/day within 6 weeks before enrollment (a common practice amongst neuro-ophthalmologists treating the ophthalmic manifestations of GCA) excluded patients from enrollment in GiACTA. Consequently, discussion among neuro-ophthalmologists regarding the use of tocilizumab has largely entailed comparison of adverse events, cost, and monitoring strategies for patients treated with tocilizumab-pluscorticosteroid vs corticosteroid monotherapy regimens (34). Several recent publications have focused on the putative impact of tocilizumab on vision preservation in GCA, both at the time of presentation with ophthalmic findings and during corticosteroid withdrawal. While the publications discussed below are far from conclusive, they prompt consideration of means by which tocilizumab might be leveraged to improve neuro-ophthalmic outcomes in GCA. Acute Stabilization of Ophthalmic Complications of Giant Cell Arteritis The goals of acute, high-dose corticosteroid treatment are to prevent worsening of vision in an initially affected eye and to prevent involvement of the fellow eye. Vision loss associated with GCA is typically severe, irreversible, and may portend rapid involvement of the initially unaffected eye (1,26,31,58). Even with prompt initiation of high-dose corticosteroids, progressive vision loss during the first week of therapy may occur in a meaningful minority of patients. In a prospective study of 34 patients, Danesh-Meyer et al reported worsening of 2 or more lines of acuity in 11 of 40 eyes (27.5%) of eyes affected by GCA during the first week of therapy despite a standardized protocol of 3 days of intravenous methylprednisolone (IVMP) at a dose of 1 gm/day before transitioning to oral therapy (26). Larger TABLE 4. Caveats to tocilizumab use Inflammatory markers are suppressed, regardless of disease activity Regular monitoring of WBC, PLT, LFTs, and cholesterol are required Vaccination should be updated if possible before tocilizumab is started Patients should be screened for latent TB infection Tocilizumab should be avoided in patients with GI tract conditions predisposing to GI perforation (e.g., history of diverticulitis), and with primary or secondary immunodeficiency GI, gastrointestinal; LFT, liver function test; WBC, white blood cell; PLT, platelet; TB, tuberculosis. Bouffard et al: J Neuro-Ophthalmol 2022; 42: 173-179 175 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review retrospective analyses have yielded similar results. Hayreh et al reported progressive vision loss in 11 eyes among 9 of 91 patients (10%) within 5 days of initiation of corticosteroids irrespective of route, although participants were not randomized (59). In a retrospective analysis of 45 patients with biopsy-proven GCA, Liu et al reported progressive vision loss in 7 of 41 patients (17%). Although corticosteroids are often administered via an intravenous rather than oral route, superiority over oral corticosteroids in the prevention of further acute vision loss has not been unequivocally demonstrated (59–62). While vision loss after 5 days of high-dose corticosteroid therapy is unusual, means of reducing the vulnerability of patients to further and potentially devastating vision loss during the first week of treatment would be desirable. Two recent case reports suggest that the addition of tocilizumab to corticosteroids may aid in the acute management of ophthalmic manifestations of GCA. Svasti-Salee et al described a 72-year-old Caucasian man who presented with a posterior ischemic optic in the right eye. Accompanying symptoms at the time of diagnosis included new-onset headaches, jaw claudication, transient diplopia, and transient monocular vision loss. Examination initially revealed acuities of 6/9 in each eye, a relative afferent pupillary defect in the right eye, dyschromatopsia in the right eye, and constriction of the visual field in the right eye. Temporal artery biopsy revealed evidence of GCA. Intravenous methylprednisolone was begun at a dose of 500 mg daily for 3 days followed by oral prednisolone at a dose of 60 mg daily. Sixteen days into treatment, vision worsened from 6/9 to handmotion with the development of pallid disc edema and CRAO in the right eye (arteriolar stasis was noted), refractory to resumption of 1 g of IVMP. Intravenous tocilizumab was begun at a dose of 8 mg/kg within 48 hours in combination with oral prednisolone at a dose of 1 mg/kg. Within 5 days, best-corrected visual acuity in the right eye returned to 20/20 with decrease in disc edema and restoration of normal flow through the central retinal artery (63). Vionnet et al described a 73-year-old Caucasian woman with biopsy-positive GCA who presented with AAION in the right eye and normal afferent visual function in the left eye with a choroidal filling defect noted on fluorescein angiography. After 3 doses of IVMP at a dose of 1 gm/day, the patient’s visual acuity worsened from light perception to no light perception in the right eye, pallid disc edema and an inferior field defect developed in the left eye, and her headache worsened. After 2 further days of IVMP, tocilizumab (via a route not clearly defined) was started at a dose of 8 mg/kg contemporaneous with a transition from IVMP to oral prednisone at a dose of 1 mg/kg daily. Initiation of tocilizumab was associated with a rapid resolution of the clinical symptoms, which had persisted despite IVMP (headache, neck pain, fatigue, night sweats, jaw claudica176 tion, and temporal allodynia). The patient’s vision remained stable following prompt administration of tocilizumab. Recognizing the limitations inherent to case reports, each of these publications suggests that intravenous tocilizumab may suppress GCA in a rapid fashion, restoring or stabilizing vision. It is important to acknowledge that tocilizumab was given in conjunction with high-dose IVMP in each case. However, full recovery from a clinically definite CRAO and AAION as exhibited by the patient presented by Svasti-Salee et al is unusual with corticosteroid monotherapy, even at high doses (60). While the patient reported by Vionnet et al did not experience restoration of vision, tocilizumab was associated with prompt resolution of multiple systemic complaints reflective of GCA, which had persisted throughout 5 days of high-dose IVMP. Caution should be employed interpreting this as a causative effect because vision loss typically stabilizes within days of corticosteroid initiation (64). Prospective, randomized investigations will be required to clearly establish whether intravenous tocilizumab augments the ability of corticosteroids to mitigate vision loss at the time of diagnosis. The cases described by Svasti-Salee et al and Vionnet et al suggested the potential for a rapid clinical response to tocilizumab as might be suspected based on the pharmacodynamics of intravenous tocilizumab and its ability to rapidly suppress inflammatory markers (65,66). Subcutaneous tocilizumab requires weeks to reach steady state in serum and is unlikely to influence neuro-ophthalmic manifestations of GCA acutely (65). Current barriers to early intravenous tocilizumab use, such as readily available drug supplies and the need to obtain insurance approval, may be better addressed when its utility has been clarified. Preventing Vision Loss in the Setting of Relapse Corticosteroid tapering following stabilization of GCA presents a second period of risk for vision loss, particularly when the daily prednisone dose is lower than 30 mg daily. The incidence of new vision loss during tapering of corticosteroid monotherapy in the published literature is variable, likely owing to heterogeneity in treatment paradigms, monitoring strategies, and definition (e.g., fixed vs transient) (5,25,30,67–69). This is illustrated by 1 retrospective analysis of 60 patients with relapsing GCA; while treated with corticosteroid monotherapy, 40.9% (9 of 22) of patients who originally presented with visual manifestations of GCA developed flares involving vision and 13.2% (5 of 38) of patients whose initial presentation did not entail visual complaints developed flares involving vision. Despite the common occurrence of flares involving vision, only 2 (3.3%) involved permanent vision loss (35). Other series have noted a higher incidence of permanent vision loss during corticosteroid tapering. Chan et al noted recurrent ischemic optic neuropathy in 10% of patients in an Australian cohort of 67 patients with AAION at the time of Bouffard et al: J Neuro-Ophthalmol 2022; 42: 173-179 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review presentation. Recurrent AAION occurred a median of 8 months (range, 3–36 months) after the initial ischemic optic neuropathy without any clear difference in baseline demographics, features of GCA, or rapidity of corticosteroid taper as compared with nonrelapsing patients. The majority of patients either reported contemporaneous headache or demonstrated an increase in erythrocyte sedimentation rate or C-reactive protein at the time of recurrent AAION. Vision loss due to recurrent AAION was not responsive to increased corticosteroid dosing (68). Regardless of the absolute risk of permanent vision loss during corticosteroid withdrawal, the available literature suggests that an important minority of patients are likely to be affected. Further mitigating vision loss during tapering of immunomodulatory therapy in GCA would require decreasing at least 1 of the following: • the risk of GCA relapse in general; • the proportion of flares involving vision loss specifically; • the risk of permanent vision loss when relapses do affect vision. Retrospective, real-world, observational evidence recently reported that the addition of tocilizumab to corticosteroid therapy may be able to accomplish all 3 of these goals (35). Unizony et al described 60 patients with relapsing GCA seen at the Massachusetts General Hospital between 2010 and 2018. The median disease duration before receiving tocilizumab was 0.6 (interquartile range [IQR], 0.2–1.6) years. Patients received tocilizumab for a median duration of 0.5 (IQR, 0.3–1.4) years. A total of 58 patients (96.7%) received concomitant prednisone (mean [SD] dose, 30 [18.3] mg daily) at the time of tocilizumab initiation. Forty-three patients (71.7%) had at least 1 relapse before initiating tocilizumab, and 18 patients (30.0%) had at least 1 relapse while on tocilizumab therapy (35). While the GiACTA trial may have excluded the typical neuro-ophthalmic patient (many of whom receive IVMP at a dose of .100 mg/day), this publication suggests that the reduction in flares demonstrated with tocilizumab likely applies to patients presenting with neuro-ophthalmic manifestations of GCA as well. Twenty-two patients with visual manifestations of GCA at the time of diagnosis experienced a reduction in flare frequency from 1.2 to 0.4 flares/ year after tocilizumab initiation, compared with a similar reduction from 1.5 to 0.6 flares/year in 38 patients without visual manifestations at diagnosis (35). The proportion of flares involving vision loss was also reduced with tocilizumab use. Fifteen of 102 flares (14.7%) before tocilizumab initiation involved typical visual manifestations of GCA (e.g., amaurosis fugax, episodic blurred vision, diplopia, and permanent vision loss), a rate that decreased to 8.1% (3/37 flares) after tocilizumab initiation. None of the flares involving afferent visual dysfunction in patients receiving tocilizumab resulted in permanent vision loss, compared with 2 flares with permanent vision loss attributed to Bouffard et al: J Neuro-Ophthalmol 2022; 42: 173-179 AAION in patients before starting tocilizumab (1 of whom had not initially presented with visual manifestations). These data are augmented by another recent publication describing 186 patients with GCA treated between 2010 and 2018 with tocilizumab and corticosteroids. The cumulative tocilizumab treatment was 224 years with a median treatment duration of 11.1 months. Corticosteroids were tapered over a median of 5.8 (IQR 3.0–8.5) months. No patients lost vision during corticosteroid tapering while on tocilizumab; 1 patient developed AAION 15 days into a study protocol involving a corticosteroid pulse therapy followed by tocilizumab monotherapy, and in a second patient, tocilizumab was added to no effect after AAION (70). These data suggest that tocilizumab may have an important role to play in optimizing neuro-ophthalmic outcomes in patients with GCA by reducing flare frequency, reducing the proportion of flares affecting vision, and likely reducing the probability of severe, permanent vision loss. CONCLUSIONS Compared with conventional corticosteroid monotherapy, treatment of GCA with both corticosteroids and tocilizumab may decrease the likelihood of permanent vision loss. Based on retrospective data, tocilizumab appears to reduce flare frequency to a similar extent regardless of whether visual manifestations of GCA were noted at the time of presentation. The proportion of GCA flares involving vision loss and the likelihood of permanent vision loss may be decreased with the addition of tocilizumab to corticosteroid therapy. Case reports, supplementing pharmacodynamic data, suggest that intravenous tocilizumab may augment corticosteroid therapy in the rapid suppression of disease activity. Future, prospective, collaborative research between neuro-ophthalmologists and rheumatologists offers the best promise of comprehensively defining tocilizumab's impact on the ophthalmic and socioeconomic ramifications of GCA. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. A. Bouffard, S. Prasad, S. Unizony; b. Acquisition of data: M. Bouffard, S. Unizony; c. Analysis and interpretation of data: M. A. Bouffard, S. Unizony; Category 2: a. Drafting the manuscript: M. A. Bouffard, S. Unizony; b. Revising it for intellectual content: M. Bouffard, S. Prasad, S. Unizony; Category 3: a. Final approval of the completed manuscript: M. A. 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