Abstract
Immune checkpoint inhibitors have revolutionized cancer therapy by blocking inhibitory pathways of the immune system to fight cancer cells. Their use is often limited by the development of autoimmune toxicities, which can affect multiple organ systems and are referred to as immune-related adverse events (irAE). Among these are rheumatologic irAE, including inflammatory arthritis, myositis, vasculitis, and others. Rheumatologic irAE seem to be different from irAE in other organs and from traditional autoimmune diseases in that they can occur early or have delayed onset, and can persist chronically, even after cancer therapy is terminated. Because immune checkpoint inhibitors are increasingly used for many types of cancer, it is important for oncologists and rheumatologists to recognize and manage toxicities early. In this review, we discuss currently approved immune checkpoint inhibitors and their mechanisms of action and systemic toxicities, with a focus on the management and effect on further cancer therapy of rheumatic irAE.
Immunotherapy has emerged as a new pillar in the treatment of cancer and has transformed outcomes of patients with previously untreatable malignancies1,2. Unlike traditional chemotherapy, which commonly has the secondary effect of immunosuppression, modern immunotherapy aims at upregulating the immune system to augment antitumor responses. Immune checkpoint inhibitors (ICI) have emerged as one of the most promising forms of immunotherapy3.
ICI increase antitumor activity by blocking intrinsic downregulators of the immune system, including T cell lymphocyte costimulation inhibitor (CTLA-4), programmed death protein-1 (PD-1), and programmed death ligand-1 (PD-L1)4. Normally, these regulatory receptors, or checkpoints, maintain the balance between T cell activation and inhibition. The primary aim of ICI is to reduce the suppression of effector T cells, particularly CD8+ T cells, improving their ability to mount tumor-specific immune responses5. CTLA-4 is upregulated early after T cell activation in central tissues including lymphoid and thymic tissues (Figure 1). It transmits an inhibitory signal to activated T cells at a proximal step in the immune response, by preferentially binding to CD80/86 expressed by antigen presenting cells (APC), thereby blocking the second signal required for T cell activation. Antibodies targeting CTLA-4 neutralize this central checkpoint, allowing ongoing T cell activation and thereby enhancing their anti-tumor activity.
Mechanism of action of immune checkpoint inhibitors.
In contrast, PD-1 is believed to play a role in T cell inhibition in the peripheral tissues, at a later stage of the immune response (Figure 1). When effector T cells encounter continuous antigen (as in chronic infection or cancer), they lose the ability to respond to the antigen — a condition known as T cell exhaustion. This is partly mediated by the enhanced expression of immune checkpoints such as PD-1. The binding of PD-1 to its ligands, PD-L1 and PD-L2 (which are expressed by many tumor cells), interferes with downstream signaling and can lead to T cell exhaustion. Antibodies that block the interaction of PD-1 with PD-L1/PD-L2 serve to neutralize this checkpoint, restoring T cell effector function5,6.
The widespread use of ICI has led to remarkable clinical outcomes, with complete remissions and sustained clinical responses seen in some patients with previously refractory cancers such as melanoma, lung cancer, renal cell carcinoma, and Hodgkin lymphoma. To date, the US Food and Drug Administration and Health Canada have approved 7 ICI (and 1 combination), which target either CTLA-4 or PD-1/PD-L1 pathways for a variety of different cancers (Table 1)7. Indications for these (either alone or in combination) continue to grow rapidly as more data become available. Other immune checkpoint pathways have also been identified and are currently being investigated for clinical use in an increasing number of cancer types and stages.
List of FDA and Health Canada–approved immune checkpoint inhibitors and their indications.
Immune-related adverse events associated with ICI
Unfortunately, activating the immune system to fight cancer can also lead to serious, undesirable off-target immune and inflammatory events known as immune-related adverse events (irAE). These have been reported in up to 80% of patients receiving monotherapy and up to 95% with combination therapy (PD-1 and CTLA-4)8,9,10,11,12. There have been higher rates reported with CTLA-4 blockade than with PD-1 blockade13. The clinical spectrum of irAE is broad and can affect multiple organ systems (Figure 2). Further, many patients can experience more than 1 irAE involving multiple organ systems11. The most common irAE include rash, colitis, thyroiditis, hypophysitis, hepatitis, pneumonitis, and arthritis, with clinical severity ranging from mild to severe and occasionally fatal. Most events occur within the first 3–4 months of therapy but can occur any time during treatment and even years after cessation of immunotherapy. Although some irAE can be transient, others require chronic immunosuppression. In addition to the morbidity of irAE, a recent metaanalysis reported a fatality rate of 1.3% and as many as a third of patients are forced to stop these potentially life-saving therapies because of toxicity14. Early symptoms are often nonspecific, including fatigue and malaise; further, many patients with cancer assume these side effects are expected and often underreport symptoms, leading to delay in diagnosis. Therefore, awareness and early recognition is essential to optimize longterm outcomes.
Systemic irAE associated with immune checkpoint inhibitors. irAE: immune-related adverse events; PMR: polymyalgia rheumatica; DRESS syndrome: Drug Rash with Eosinophilia and Systemic Symptoms syndrome.
Rheumatic irAE
Rheumatic irAE (Rh-irAE) secondary to immunotherapy are likely underreported in clinical trials with the majority of our knowledge coming from case reports and case series15. Thus, our understanding of the prevalence, incidence, clinical features, optimal management, and prognosis of Rh-irAE continues to evolve with ongoing clinical experience. In early clinical trials, arthralgias and myalgias were the most commonly reported Rh-irAE, with a prevalence of 1–43% and 2–20%, respectively16. With the increased use of ICI in clinical practice, a wide range of Rh-irAE have been described, most commonly inflammatory arthritis, but also myositis, vasculitis, new-onset fractures, resorptive bone lesions, sicca syndrome, and sarcoidosis17,18,19.
Inflammatory arthritis
Inflammatory arthritis secondary to ICI (ir-IA) has been described in several case series and retrospective cohort studies6,17,18,20–24. The prevalence was reported as 3.8% in one study18. The most common patterns include (1) polymyalgia rheumatica (PMR)-like (shoulder and pelvic girdle stiffness), (2) small joint symmetric inflammatory arthritis (predominantly hand) with diffuse tenosynovitis, and (3) large joint, asymmetric oligoarthritis, predominantly involving the knees. In addition, there have been reported cases of a reactive arthritis–like triad (urethritis, conjunctivitis, and arthritis)17, and psoriatic arthritis.
Ir-IA may be different from the classic inflammatory rheumatic diseases that they mimic and may have differing longterm outcomes. There has been no predilection by sex reported, with generally equal cases in men and women. The majority of cases have been seronegative [although rheumatoid factor (RF)-positive and cyclic citrullinated peptide antibodies (CCP)–positive cases have been reported], with high prevalence of enthesitis/tenosynovitis that often requires higher doses of corticosteroids than traditionally used. Although ir-IA have been reported after 1 dose, they can occur up to 2 years after immunotherapy and can often become chronic, despite stopping immunotherapy, unlike other irAE such as colitis and pneumonitis. Joint involvement pattern at baseline, severity of symptom onset, and requirement of longterm immunosuppression may differ by the underlying immunotherapy regimen25.
In one case series of 26 patients of European descent with ir-IA, researchers found that there was a higher prevalence of shared epitope (SE) alleles and DRB1*04:05 compared to population controls, and similar prevalence of at least 1 SE allele compared to rheumatoid arthritis patients of European descent. Interestingly, despite being SE-positive, these patients were negative for RF and CCP antibody, which raises questions regarding potential underlying mechanisms. Further, they found certain clinical features (enthesitis, trigger fingers, inflammatory low back pain, reactive arthritis) only in patients lacking SE alleles. Research is needed to determine whether distinct HLA alleles are associated with unique ir-IA phenotypes, and their risk of development26.
In addition to inflammatory arthritis (presenting with synovitis), there is emerging literature on a subset of patients with inflammatory-type joint pain without synovitis6,22. In our experience24, similar to that reported in the literature, these patients can present with debilitating pain and progressive osteophytosis, which responds to low-dose corticosteroid and antimalarial therapy.
Myositis
Myositis is an increasingly recognized irAE (ir-Myositis), although it remains relatively uncommon, affecting < 1% of patients exposed to ICI27,28. Ir-Myositis offers some unique insights into traditional autoimmune myositides (AIM). First, if ICI are considered as a class, this “single” exposure can recapitulate a broad spectrum of AIM, including dermatomyositis29,30,31, necrotizing myositis27,32, and granulomatous myositis33. This supports the observation that the same exposure could be responsible for more than 1 traditional AIM. On the other hand, ir-Myositis has been reported to overlap with myocarditis and myasthenia gravis34,35 much more frequently than when observed in the setting of traditional AIM36. Similarly, although myositis has been reported to occur in 5% of patients with thymomas, in one series of 8 patients with thymoma treated with avelumab, 4 (50%) developed myositis37. Finally, most (though not all)27,31 cases of ir-Myositis from ICI reported to date have been seronegative37,38,39. Thus, myositis from irAE probably has important differences from traditional AIM and a subset of ir-Myositis may represent a new entity.
In one of the most detailed series to date (n = 10), Touat, et al described a unique constellation of features that characterize ir-Myositis as follows: (1) early (within 2 mos of ICI initiation) and severe onset of symptoms; (2) limb-girdle weakness associated with myalgias, as well as axial and oculomotor weakness; (3) striking creatinine kinase elevations with myopathic changes on electromyography; (4) absence of myositis-specific and antiacetylcholine receptor antibodies; (5) necrosis and inflammation on histopathology; and (6) good response to ICI discontinuation with or without corticosteroids39.
Ir-Myositis tends to occur early, often after the first or second dose of ICI. Ir-Myositis ranges from mild, with some cases resolving spontaneously upon discontinuation of the offending drug39, to severe peripheral and respiratory weakness requiring mechanical ventilation40. Although myositis represents one of the less common irAE, it is associated with a high case fatality rate (17%), second only to myocarditis (39.7%)14. Mortality in cases of ir-Myositis overlapping with myocarditis or other neuromuscular symptoms is even higher (over 50% in one study)41, and results from cardiac or respiratory failure30,39.
Recognizing myositis from ICI is, in most cases, straightforward, with patients generally presenting with rapidly progressing proximal muscle weakness and elevated muscle enzymes. Other symptoms include distal, axial, and oculobulbar weakness; dysphagia, diaphragmatic weakness, and rash27,39,42. However, diagnosis may be delayed, with some patients attributing their symptoms to their cancer and related problems. Further, ir-Myositis may be difficult to distinguish from cancer-associated myositis, myocarditis, and myasthenia gravis. Finally, elevated liver enzymes have been mistakenly attributed to hepatitis, which is a more common irAE than myositis43. In general, a high level of clinical suspicion is essential given the high risk of mortality, and muscle biopsy may be required.
Vasculitis
Cases of vasculitic irAE (ir-Vasculitis) affecting the large-, medium-, or small-size vessels have been reported. A large pharmacovigilance study and a systematic review published in 2018 identified numerous cases of vasculitis44,45. Most frequent were large-vessel vasculitis, including giant cell arteritis (GCA) and isolated aortitis, and nervous system vasculitis, including primary angiitis of the central nervous system and peripheral nerve involvement. The median duration of ICI therapy preceding symptom onset was 3 months, ranging from 1 week to 18 months after initial ICI exposure. Several other cases of vasculitis have been described, including 2 cases of acral vasculitis causing digital necrosis with amputation of the distal digits despite aggressive immunosuppression46. Proteinase 3–antineutrophil cytoplasmic antibodies granulomatosis with polyangiitis (GPA) was described in a patient following sequential treatment with ipilimumab, then pembrolizumab47. Single-organ vasculitis of the uterus48, eye49,50, and skin51 have also been reported. Interestingly, a patient with eosinophilic GPA was successfully treated with ipilimumab, then pembrolizumab for metastatic melanoma without a vasculitis flare52.
There seems to be little difference between the clinical, biological, or histopathological presentation of ir-Vasculitis and idiopathic forms of these diseases. The predominance of large-vessel vasculitis also fits with the PD-1/PD-L1 pathway dysfunction in GCA highlighted by the work of Zhang, et al53. They showed that the tissue microenvironment of GCA lacks the inhibitory ligand PD-L1 and enriches for PD-1 expressing T cells. Inhibiting the PD-1/PD-L1 interaction intensified T cell accumulation in the vessel wall and profoundly enhanced tissue inflammation and remodeling of the vessel wall, affecting the process of neoangiogenesis and intimal hyperplasia. ICI iatrogenically produce a similar effect and could therefore accelerate the autoimmune process in the GCA microenvironment.
General principles for management of irAE
The Common Terminology Criteria for Adverse Events (CTCAE) can be used to grade the severity of AE and help guide management decisions (Table 2)54. Grades 1 and 2 are considered mild, grades 3 and 4 are severe, and grade 5 indicates that the patient died of an AE. In the past few years, multiple groups including the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group, the European Society of Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO) have released clinical guidelines on management of irAE secondary to immunotherapy, based on expert consensus10,55,56,57,58. The goal of treatment is to carefully balance immune function by administering enough immunosuppression to treat AE and prevent organ damage, without mitigating the antitumor effects of immunotherapy.
Common Terminology Criteria for Adverse Events grades (v. 5).
Successful management of patients with irAE requires a multidisciplinary, patient-centered approach. Champiat, et al proposed a practical approach to management of patients receiving immunotherapy including prevention, anticipation, detection, treatment, and ongoing monitoring10.
Referral to rheumatology
Because delay in diagnosis and treatment of Rh-irAE can lead to longterm disability and disease chronicity, it is important to identify those at risk and refer them early to rheumatology. SITC guidelines have recommended rheumatology referral for any patient with (1) joint swelling, (2) CTCAE grade 2 and above symptoms, (3) symptoms persisting for more than 6 weeks or requiring prednisone 20 mg daily or equivalent that cannot be tapered to < 10 mg/day within 4 weeks, and (4) suspected myositis, presenting with muscle weakness and elevated creatinine.
The decision regarding earlier rheumatology referral depends on geographic variation, oncologist comfort and experience with rheumatic disease, and availability of local rheumatologists. Ideally, we recommend referral to rheumatology for patients with any rheumatic symptoms (Grade 1 or higher) prior to starting prednisone. We encourage oncologists to develop referral relationships with 1 or 2 local rheumatologists. This will facilitate urgent evaluation of patients and allow the rheumatologist to accrue clinical experience with immunotherapy-related toxicity, leading to improved patient care.
Management of patients with Rh-irAE
The role of the rheumatologist is to diagnose and optimize management of Rh-irAE to facilitate ongoing immunotherapy, if indicated, for the underlying cancer.
It is important for rheumatologists to remember that generalized musculoskeletal symptoms (myalgia, arthralgia, weakness) can be associated with underlying cancer, preexisting arthritis, metastatic disease, infection, or side effects of other medications. They can also occur with other irAE including endocrine, gastrointestinal, and neurological types. Therefore, evaluation of patients requires a careful history and physical examination and familiarity with possible AE involving various systems and organs. Inflammatory markers including C-reactive protein are often helpful biomarkers for diagnosis and monitoring response to therapy, but can be elevated because of underlying malignancy or other nonrheumatic irAE. Radiographs can be helpful to evaluate for erosive disease and exclude metastases. Laboratory tests, biopsies, and autoimmune serologies are recommended as directed by the clinical phenotype. In those with ir-Myositis, careful evaluation for myocarditis and myasthenia gravis should be undertaken.
Current management guidelines released by ASCO, ESMO, and SITC recommend treatment based on severity of clinical presentation. There are currently no clinical trials of optimal management, and the majority of recommendations are based on expert consensus. For those with mild symptoms (Grade 1), conservative management with analgesics and nonsteroidal antiinflammatory drugs is recommended without interruption of immunotherapy. For large joint involvement, intraarticular corticosteroid injection may be beneficial59.
For Grade 2 reactions, oral corticosteroids are recommended (0.5–1.0 mg/kg/d), tapering over 4–6 weeks, while holding ICI therapy. If prednisone taper is not tolerated, disease-modifying antirheumatic drugs (DMARD) should be started, depending on clinical presentation. In our experience, some patients with ir-IA have a good response to low-dose (10–20 mg) prednisone and can tolerate ongoing ICI therapy, particularly with concurrent DMARD therapy.
For Grade 3 or above reactions, high-dose oral or intravenous corticosteroids are recommended, with permanent discontinuation of ICI. Patients should be monitored closely, either in hospital or with close outpatient followup, until resolution of symptoms. Early use of concomitant steroid-sparing agents may be needed, depending on clinical presentation and response to corticosteroids. The choice of agent usually depends on the type of irAE.
Because ir-IA tends to be chronic, we recommend earlier initiation of DMARD. Hydroxychloroquine, sulfasalazine, methotrexate (MTX), tumor necrosis factor inhibitors (TNFi), and interleukin 6 inhibitors have all been used successfully for inflammatory arthritis19,60,61. The choice of DMARD for ir-IA depends on severity of symptoms, patient preference, and access to medication. Mycophenolate mofetil (MMF) has been used preferentially for hepatitis, while TNFi are commonly used for colitis. Intravenous immunoglobulin, plasmapheresis, MTX, azathioprine, and MMF have been used for myositis39,62, and cyclophosphamide and plasmapheresis have been used for vasculitis44.
The decision to restart immunotherapy depends on type and severity of irAE, stage and response of underlying malignancy, and alternative treatment options, and should be done on a case-by-case basis with the patient and oncologist. In general, further immunotherapy is not recommended for those with Grade 3 or higher AE but may be necessary if there are no other options for underlying malignancy. One patient who developed dermatomyositis after ipilimumab was re-challenged with the same drug 14 months after discontinuation because of tumor recurrence. She had a flare of the dermatomyositis31. In contrast, 2 patients who developed ir-Myositis were re-challenged because of tumor progression, 1 with the same drug (avelumab) and the other with an alternative drug (ipilimumab/nivolumab replaced by pembrolizumab). Neither had a recurrence of myositis63.
Effect of irAE treatment on cancer outcomes
There are no prospective, randomized controlled trials evaluating whether concomitant immunosuppressive therapy negates the anti-tumor response of immunotherapy. Although most data suggest that the use of corticosteroid treatment is not associated with adverse tumor response64,65,66, recent reports have suggested that there may be an association with negative tumor response, particularly at higher doses62,67. No undesirable tumor effects have been reported with use of MMF, infliximab, or MTX16,65,66. These data come from small, retrospective studies, with potential for significant bias. Longterm data are needed, in larger populations, across various cancer types, and manifesting with different AE.
Most guidelines recommend cessation of immunotherapy in patients with grade 2 or higher AE. This can lead to anxiety regarding progression of the underlying malignancy. Nevertheless, Schadendorf, et al found that despite discontinuing immunotherapy (nivolumab plus ipilimumab) because of adverse events, patients had longterm tumor responses similar to those who continued therapy68. Further, in a followup study, they found that patients whose cancer progressed after discontinuing immunotherapy were able to regain a favorable response with restarting treatment, with a similar toxicity profile69.
All currently published guidelines recommend cessation of immunotherapy with active AE requiring systemic immunosuppression. There is little experience with combination of longterm immunosuppression with ongoing immunotherapy. That said, our preference (similar to others in the literature22) is to continue immunotherapy in patients with inflammatory arthritis, because these respond to corticosteroids and disease-modifying drugs. More research is needed to understand the complex interactions and clinical implications involved in the longterm care of these patients.
A common clinical question is whether the development of irAE predicts a favorable tumor response. This would certainly make sense because it implies that immunotherapy has done its job in “turning on” the immune system to fight cancer, thus leading to an autoimmune reaction. The answer to this remains a topic of debate9. Many clinical studies have found a correlation between the development of irAE and favorable cancer outcomes66,70–76. This seems to be independent of tumor type (reported in melanoma, renal cell carcinoma, lung cancer), type of immunotherapy (observed for both PD-1 and CTLA-4 inhibitors), or type of adverse event (seen with endocrinopathies, vitiligo, colitis, arthritis, etc.). However, this finding has not been universal. A retrospective study of ipilimumab in 298 melanoma patients found no difference in tumor response between those who developed irAE and those who did not77. Further research is needed to conclusively answer this question.
Preexisting rheumatic disease
Patients with autoimmune disease (AID) were largely excluded from clinical trials, making cancer treatment decisions in these patients challenging78. A large systematic review of 123 patients with preexisting AID treated with ICI has been published79. Of these, 72 (59%) had rheumatologic conditions including inflammatory arthritis, sarcoidosis, vasculitis, spondyloarthritis, Behçet disease, myositis, PMR, systemic lupus erythematosus, rheumatic fever, and Sjögren syndrome. Overall, about 50% had exacerbation of the preexisting AID and 34% had de novo irAE. The occurrence of AE was not different between patients with active versus inactive preexisting AID, but fewer AE were seen in patients receiving therapy for their AID at the time of ICI initiation. Overall, 17.1% discontinued ICI permanently because of AE.
Additionally, Menzies and colleagues reported a retrospective review of 52 patients with preexisting AID, of which 27 (52%) were classified as rheumatologic, who were treated with anti–PD-1 therapy for advanced melanoma80. The overall tumor response rate was 33%. Thirty-eight percent had a flare of their underlying AID requiring immunosuppression, and only 4% discontinued ICI because of their AID flare. More recently, a study of 16 patients with preexisting rheumatic disease were treated with ICI. Of these, 6 (38%) experienced an irAE, with only 1 (6%) having a flare of the underlying rheumatologic disease81.
These reports show that ICI can be used successfully in patients with AID. The response rate and incidence of AE is still unclear and prospective studies are needed in patients with preexisting AID. Nevertheless, experts agree that having a preexisting AID is not an absolute contraindication for treatment with ICI. This challenging treatment decision should be made on a case-by-case basis with collaborative consultation among patient, oncologist, rheumatologist, and other specialists. Rheumatologists have an important role in the initial assessment of disease activity, treatment, and close monitoring of the underlying autoimmune disease. Further studies are needed to answer important questions such as effect of concomitant immunosuppressive therapy on tumor response, potential biomarkers to predict irAE, and optimal preventive and treatment strategies for patients with underlying autoimmune disease.
In the last decade, ICI have changed the model of cancer care. They now have an established role in all phases of cancer treatment, from (neo)adjuvant settings all the way to refractory metastatic disease, in an ever-growing number of indications. The enhancement of immune responses with ICI has led to the emergence of irAE. Much of the initial focus of irAE identification and management was on rash, colitis, and endocrinopathies, in part because these are more common and in part because they can be associated with significant morbidity.
To date, the importance and recognition of Rh-irAE has lagged. There are several reasons for this, including (1) many symptoms of Rh-irAE, including arthralgias and myalgias, can be mistakenly attributed to the underlying malignancy, (2) treating physicians may have difficulty recognizing synovitis or may underestimate the severity of the symptoms, (3) symptoms are often delayed, and (4) symptoms are unlikely to require hospitalization or be life-threatening. As awareness increases and experience accumulates, we are learning more about rheumatic irAE and their management. As experts in systemic autoimmune disease, rheumatologists are well suited to be important members of the team in identifying and treating patients with irAE and assisting with systemic immunosuppression.
There are also many outstanding questions and significant opportunities for education and research in the field of Rh-irAE. Thus, the Canadian Research Group of Rheumatology in Immuno-Oncology was created to share knowledge, develop rheumatology-specific management guidelines, and undertake studies to define the natural history and optimal treatment of Rh-irAE. The potential to compare and contrast Rh-irAE with traditional AID and to gain further insight into the latter is also an exciting prospect and bodes well for future collaborations with other established Canadian and international rheumatology cohorts.
Footnotes
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- Accepted for publication June 28, 2019.
Free online via JRheum Full Release option
REFERENCES
- 1.↵
- 2.↵
- 3.↵
- 4.↵
- 5.↵
- 6.↵
- 7.↵
- 8.↵
- 9.↵
- 10.↵
- 11.↵
- 12.↵
- 13.↵
- 14.↵
- 15.↵
- 16.↵
- 17.↵
- 18.↵
- 19.↵
- 20.↵
- 21.
- 22.↵
- 23.
- 24.↵
- 25.↵
- 26.↵
- 27.↵
- 28.↵
- 29.↵
- 30.↵
- 31.↵
- 32.↵
- 33.↵
- 34.↵
- 35.↵
- 36.↵
- 37.↵
- 38.↵
- 39.↵
- 40.↵
- 41.↵
- 42.↵
- 43.↵
- 44.↵
- 45.↵
- 46.↵
- 47.↵
- 48.↵
- 49.↵
- 50.↵
- 51.↵
- 52.↵
- 53.↵
- 54.↵
- 55.↵
- 56.↵
- 57.↵
- 58.↵
- 59.↵
- 60.↵
- 61.↵
- 62.↵
- 63.↵
- 64.↵
- 65.↵
- 66.↵
- 67.↵
- 68.↵
- 69.↵
- 70.↵
- 71.
- 72.
- 73.
- 74.
- 75.
- 76.↵
- 77.↵
- 78.↵
- 79.↵
- 80.↵
- 81.↵
